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Sample records for intracerebroventricularly injected insulin

  1. 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.

  2. 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

  3. Insulin Injection

    MedlinePlus

    ... to control blood sugar in people who have type 1 diabetes (condition in which the body does not make insulin and therefore cannot control the amount of sugar in the blood) or in people who have type 2 diabetes (condition in which the blood sugar ...

  4. 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

  5. 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.

  6. 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

  7. Diffusion and action of intracerebroventricularly injected interleukin-1 in the CNS.

    PubMed

    Konsman, J P; Tridon, V; Dantzer, R

    2000-01-01

    Interleukin-1beta acts on the CNS to induce fever, neuroendocrine activation and behavioural depression. We have previously demonstrated that interleukin-1beta is synthesized in glial cells and macrophages of circumventricular organs and choroid plexus after intraperitoneal administration of bacterial lipopolysaccharide. Whether, and how, interleukin-1beta produced in glial cells affects neuronal functioning is unknown. Diffusion throughout the extracellular space is an important pathway by which factors produced by glial cells act on distant cells, a phenomenon coined "volume transmission". The present study assessed diffusion of recombinant rat interleukin-1beta, recombinant human interleukin-1 receptor antagonist and 10mol. wt dexran in the rat CNS after intracerebroventricular administration to model interleukin-1beta release from choroid plexus. Immunocytochemistry with specific antibodies directed against interleukin-1beta and interleukin-1 receptor antagonist revealed that these molecules rapidly penetrated into periventricular tissue and spread along white matter fibre bundles and blood vessels in the caudoputamen, hypothalamus and amygdala. The transcription factor nuclear factor kappa B and the immediate-early gene product Fos were detected immunocytochemically to reveal interleukin-1beta action. Intracerebroventricular infusion of interleukin-1beta induced nuclear factor kappa B translocation in choroid plexus, ependymal cells, basolateral amygdala, cerebral vasculature and meninges. Fos immunoreactivity was found in the supraoptic and paraventricular hypothalamus and central amygdala. We propose that intracerebroventricular injected interleukin-1beta can enter the brain parenchyma and act as a "volume transmission" signal in, for example, the basolateral amygdala where it might activate a neuronal projection to the central amygdala.

  8. 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 ...

  9. Insulin Lispro 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 ...

  10. 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

    2016-01-01

    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. PMID:27501398

  11. Subcutaneous or intramuscular insulin injections.

    PubMed Central

    Smith, C P; Sargent, M A; Wilson, B P; Price, D A

    1991-01-01

    To find out whether diabetic children may inject their insulin intramuscularly rather than subcutaneously, a random sample of 32 patients aged 4.3-17.9 (median 11.3) years was studied. Distance from skin to muscle fascia was measured by ultrasonography at standard injection sites on the outer arm, anterior and lateral thigh, abdomen, buttock, and calf. Distances were greater in girls (n = 15) than in boys (n = 17). Whereas in most boys the distances were less than the length of the needle (12.5 mm) at all sites except the buttock, in most girls, the distances were greater than 12.5 mm except over the calf. Over the fascial plane just lateral to the rectus muscle the distance from skin to peritoneum was less than 12.5 mm in 14 of the 17 boys and one of the 15 girls. Twenty five of the 32 children injected at an angle of 90 degrees, and 24 children raised a skinfold before injecting. By raising a skinfold over the anterior thigh, the distance from skin to muscle fascia was increased by 19% (range 0-38%). We conclude that most boys and some girls who use the perpendicular injection technique may often inject insulin into muscle, and perhaps on occasions into the peritoneal cavity. PMID:1863105

  12. Renal effects of intracerebroventricularly injected tachykinins in the conscious saline-loaded rat: receptor characterization

    PubMed Central

    Ding Yuan, Yi; Couture, Réjean

    1997-01-01

    The effects of intracerebroventricularly (i.c.v.) injected substance P (SP), neurokinin A (NKA) and [MePhe7]neurokinin B (NKB) were investigated on renal excretion of water, sodium and potassium in the conscious saline-loaded rat. The central effects of [MePhe7]NKB were characterized with selective tachykinin antagonists for NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 820) receptors.Whereas SP or NKA (65 or 650 pmol) failed to modify the renal responses, [MePhe7]NKB (65–6500 pmol) produced dose-dependent and long-lasting (30–45 min) decreases in renal excretion of water (maximal reduction at 65 pmol: from 66.14±7.62 to 21.07±3.79 μl min−1), sodium (maximal reduction at 65 pmol: from 10.19±2.0 to 1.75±0.48 μmol min−1) and potassium (maximal reduction at 65 pmol: from 4.31±1.38 to 0.71±0.27 μmol min−1). While 650 pmol [MePhe7]NKB elevated urinary osmolality, neither 65 pmol nor 6.5 nmol [MePhe7]NKB altered this parameter.Both the antidiuresis and antinatriuresis induced by [MePhe7]NKB (65 pmol) were significantly blocked by the prior i.c.v. injection of R 820 (1.3 nmol, 5 min earlier), although the potassium excretion was only partially reduced. However, R 820 did not affect the antidiuresis and antinatriuresis elicited by endothelin-1 (1 pmol, i.c.v.). On its own, R 820 decreased renal potassium excretion with no effect on urinary osmolality and renal excretion of water and sodium. The i.c.v. co-injection of RP 67580 and SR 48968 (6.5 nmol each, 5 min earlier) failed to modify the renal responses to [MePhe7]NKB in a similar study.The central effects of [MePhe7]NKB (65 pmol) on renal excretion were blocked by the prior i.v. administration of a linear peptide vasopressin V2 receptor antagonist (50 μg kg−1, 5 min earlier).These results suggest that the central NK3 receptor, probably located in the hypothalamus, is implicated in the renal control of water and electrolyte homeostasis through the release of

  13. 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

  14. 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. PMID:25616225

  15. 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. PMID:25120202

  16. 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.

  17. 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.

  18. Effect of intracerebroventricular injections of prolactin-releasing peptide on prolactin release and stress-related responses in steers.

    PubMed

    Kitagawa, Sayuki; Abe, Naoshige; Sutoh, Madoka; Kasuya, Etsuko; Sugita, Shoei; Aoyama, Masato; Yayou, Ken-ichi

    2011-04-01

    Some evidence suggests that there might be a species difference in the effect of intracerebroventricularly administered (ICV) prolactin-releasing peptide (PrRP) between rodents and sheep. We compared the levels of cortisol (CORT) and prolactin (PRL), rectal temperature (RT) and behavioral responses to ICV bovine PrRP (bPrRP) in steers. ICV bPrRP (0.2, 2 and 20 nmol/200 µL) tended to evoke a dose-related increase in CORT concentrations and 0.2 nmol of bPrRP induced transient increase in PRL concentrations. A significant time-treatment interaction was observed for the percent change of CORT (P<0.05) and PRL (P<0.05) from pre-injection value. The time-treatment interaction for changes in RT was not significant (P=0.50). There tended to be a difference among the four treatments in terms of maximum change in RT from the pre-injection value between 0 and 90 min (P<0.1). Stress-related behavioral signs were not observed in the present experiment. These findings indicate that ICV bPrRP increased CORT and PRL levels, suggesting that central PrRP might participate in controlling the hypothalamo-pituitary-adrenal axis and PRL release in cattle, unlike sheep. In contrast, central PrRP is unlikely to be involved in controlling the behavior of this species because ICV bPrRP did not induce marked changes in their behavior.

  19. Intracerebroventricular injection of N omega-nitro-L-arginine in rats impairs learning in a 14-unit T-maze.

    PubMed

    Ingram, D K; Spangler, E L; Kametani, H; Meyer, R C; London, E D

    1998-01-01

    We investigated whether intracerebroventricular (i.c.v.) infusion of the nitric oxide synthase inhibitor, Nomega-nitro-L-arginine (N-Arg), impairs learning in male Sprague-Dawley rats (2-3 months old) in a 14-unit T-maze. Rats were pretrained in one-way active avoidance to a criterion of 13/15 avoidances of foot shock in a straight runway. The next day, rats received i.c.v. injections of either artificial cerebrospinal fluid (aCSF) as controls or N-Arg (12 microg or 15 microg) 30 min before training in the 14-unit T-maze. The learning contingency was to negotiate each of 5 segments within 10 s to avoid footshock during 15 trials. Performance variables included errors (deviations from the correct pathway), runtime from start to goal, and shock frequency and duration. Compared to controls, the number of errors over the last 10 trials was higher in rats receiving 15 microg N-Arg and over the last 5 trials for those given 12 microg. Runtime, shock frequency and duration were increased in both N-Arg groups. The N-Arg-induced (15 microg i.c.v.) impairment could be attenuated when the nitric oxide donor, sodium nitroprusside (1 mg/kg), was administered intraperitoneally 1 min prior to maze learning. In a retention test, rats were treated with either aCSF or 15 microg N-Arg i.c.v. 30 min before being retested in the maze 7-10 d following acquisition training. Under these conditions, maze performance was not significantly affected. These results confirmed previous findings that inhibition of nitric oxide synthase impairs acquisition but not retention. Moreover, the N-Arg-induced learning impairment does not appear to be related to noncognitive aspects of performance. PMID:9489850

  20. 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.

  1. 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.

  2. Painful fat necrosis resulting from insulin injections

    PubMed Central

    Pandit, M; Menon, V; Roberts, S; Barber, T M

    2014-01-01

    Summary The case is a 34-year-old woman with long-standing type 1 diabetes mellitus with existing follow-up in the outpatient clinic at the Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, UHCW. She had maintained good glycaemic control and glycaemic stability with basal bolus regimen for many years. She had not developed any diabetes-related complications and had no other co-morbidities. Six months ago, she presented to A&E with sudden-onset, well-localised and severe pain in the right iliac fossa, just lateral to the para-umbilical area. Her biochemistry was normal. Ultrasound scan, however, revealed a right-sided ovarian cyst, which was thought to have caused pain to her. She was discharged from A&E with simple analgesia. On subsequent gynaecological follow-up 4 weeks later, her pain remained severe and examination revealed an exquisitely tender subcutaneous nodule at the same location measuring 2 cm in diameter. Magnetic resonance imaging (MRI) scan at the time revealed a 1 cm mass in the subcutaneous adipose tissue, which co-localised to her pain. The mass demonstrated a central fat signal surrounded by a peripheral ring: observations consistent with fat necrosis. There were other smaller subcutaneous nodules also observed in the left para-umbilical area. Subsequent surgical resection of the main area of fat necrosis was performed. The patient made an excellent recovery and her pain resolved post-operatively. Histology confirmed the presence of fat necrosis. Fat necrosis is a rare complication of s.c. insulin injection. This case illustrates the importance of considering this diagnosis in patients who inject insulin and develop localised injection-site pain. Learning points Fat necrosis is a rare complication of insulin injections that can manifest with severe, persistent and well-localised pain.Fat necrosis can masquerade as other pathologies causing diagnostic confusion.The imaging modality of choice for accurate diagnosis

  3. Insulin Glulisine (rDNA origin) Injection

    MedlinePlus

    ... is a short-acting, man-made version of human insulin. Insulin glulisine works by replacing the insulin ... medications for asthma and colds; certain medications for human immunodeficiency virus (HIV) including amprenavir (Agenerase), atazanavir (Reyataz), ...

  4. Effect of intracerebroventricular continuous infusion of valproic acid versus single i.p. and i.c.v. injections in the amygdala kindling epilepsy model.

    PubMed

    Serralta, Alfonso; Barcia, Juan A; Ortiz, Pedro; Durán, Carmen; Hernández, M Eugenia; Alós, Manuel

    2006-07-01

    Two protocols were tested to assess anticonvulsant efficacy and drug concentrations after intracerebroventricular (i.c.v.) continuous valproic acid (VPA) infusion, as compared with acute injections in the kindling epilepsy model. Protocol 1: amygdala-kindled rats were injected via intraperitoneal (i.p.) and i.c.v. routes with varying doses of VPA and tested for seizure intensity, afterdischarge and seizure duration, ataxia and sedation. Concentrations of VPA were determined by immunofluorescence in the brain, plasma, cerebrospinal fluid (CSF) and liver in matching rats. Protocol 2: amygdala-kindled rats were implanted with osmotic minipumps containing a VPA solution in saline and connected to intraventricular catheters for 7 days. Seizure threshold, latency and duration, afterdischarge duration, ataxia and sedation were recorded daily before, during, and until 5 days after VPA infusion. In matching animals, CSF, brain, plasma and liver VPA concentration was determined. Acute i.c.v. VPA injection suppressed seizures with a remarkable ataxia and sedation. However, continuous i.c.v. infusion controlled generalised and even focal seizures without producing important side effects, high plasma levels or hepatic drug concentrations. In conclusion, continuous i.c.v. VPA infusion may protect against kindled seizures by minimising ataxia and sedation, and achieving suitable intracerebral, yet low plasma or hepatic drug concentrations, thus avoiding potential systemic toxicity.

  5. The mediation of the central histaminergic system in the pressor effect of intracerebroventricularly injected melittin, a phospholipase A2 activator, in normotensive rats.

    PubMed

    Altinbas, Burcin; Topuz, Bora B; Yilmaz, Mustafa S; Aydin, Cenk; Savci, Vahide; Jochem, Jerzy; Aydin, Sami; Yalcin, Murat

    2012-01-01

    Melittin is a polypeptide component of bee venom that leads to an increase in arachidonic acid release and subsequently in prostaglandin synthesis by activating phospholipase A(2). Recently we demonstrated that centrally or peripherally administrated melittin caused pressor effect and central thromboxane A(2) (TXA(2)) and cholinergic system mediated these effects of melittin. Also centrally injected histamine leads to pressor and bradycardic response by activating central histamine receptors in normotensive rats and central cholinergic system involved the effects of histamine. The present study demonstrates an involvement of the central histaminergic system in melittin-induced cardiovascular effect in normotensive rats. Experiments were carried out in male Sprague Dawley rats. Intracerebroventricularly (i.c.v.) injected melittin (0.5, 1 and 2 nmol) caused dose- and time-dependent increases in mean arterial pressure (MAP) and decrease in heart rate (HR) as we reported previously. Moreover, H(2) receptor antagonist ranitidine (50 nmol; i.c.v.) almost completely and H(3)/H(4) receptor antagonist thioperamide (50 nmol; i.c.v.) partly blocked melittin-evoked cardiovascular effects, whereas H(1) receptor blocker chlorpheniramine (50 nmol; i.c.v.) had no effect. Also centrally injected melittin was accompanied by 28% increase in extracellular histamine concentration in the posterior hypothalamus, as shown in microdialysis studies. In conclusion, results show that centrally administered melittin causes pressor and bradycardic response in conscious rats. Moreover, according to our findings, there is an involvement of the central histaminergic system in melittin-induced cardiovascular effects.

  6. Insulin Glargine (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 ...

  7. Insulin Aspart (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 ...

  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. Insulin Degludec (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 ...

  10. Attempted suicide by insulin injection treated with artificial pancreas.

    PubMed Central

    Gin, H; Larnaudie, B; Aubertin, J

    1983-01-01

    An elderly woman with longstanding insulin dependent diabetes tried to commit suicide by injecting 400 units of insulin subcutaneously (usual total daily dose 56 units). She was admitted to hospital within the hour and treated with the aid of an artificial pancreas. This avoided the usual difficulty of the physician having to cope with rapid and substantial fluctuations in blood glucose concentrations and 67 hours after the overdose insulin was reinstituted. Using an artificial pancreas in insulin overdose is an important advance in management and may avoid the need for surgical intervention such as excising the site of injection. Images p250-a PMID:6409269

  11. Forum for Injection Techniques, India: The First Indian Recommendations for Best Practice in Insulin Injection Technique

    PubMed Central

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

    2012-01-01

    Advances in the treatment of diabetes have led to an increase in the number of injectable therapies, such as human insulin, insulin analogues, and glucagon-like peptide-1 analogues. The efficacy of injection therapy in diabetes depends on correct injection technique, among many other factors. Good injection technique is vital in achieving glycemic control and thus preventing complications of diabetes. From the patients’ and health-care providers’ perspective, it is essential to have guidelines to understand injections and injection techniques. The abridged version of the First Indian Insulin Injection technique guidelines developed by the Forum for Injection Technique (FIT) India presented here acknowledge good insulin injection techniques and provide evidence-based recommendations to assist diabetes care providers in improving their clinical practice. PMID:23226630

  12. Intraperitoneal insulin therapy for a patient with type 1 diabetes with insulin injection site inflammation

    PubMed Central

    Lee, Siang Ing; Narendran, Parth

    2014-01-01

    A 36-year-old man with type 1 diabetes developed skin inflammation at the site of subcutaneous insulin injection after 10 years of basal bolus subcutaneous insulin therapy. This inflammation led to poor insulin absorption, poorly controlled blood glucose and subsequently to ketoacidosis. The problem persisted despite a trial of continuous subcutaneous insulin infusion. The patient went on to be treated with continuous intraperitoneal insulin infusion. Three months after the procedure, he was achieving good glucose control and was able to resume his normal life, with the only complication being an episode of cellulitis surrounding the port site. PMID:25188930

  13. Systemically modeling the dynamics of plasma insulin in subcutaneous injection of insulin analogues for type 1 diabetes.

    PubMed

    Li, Jiaxu; Kuang, Yang

    2009-01-01

    Type 1 diabetics must inject exogenous insulin or insulin analogues one or more times daily. The timing and dosage of insulin administration have been a critical research area since the invention of insulin analogues. Several pharmacokinetical models have been proposed, and some are applied clinically in modeling various insulin therapies. However, their plasma insulin concentration must be computed separately from the models' output. Furthermore, minimal analytical study was performed in these existing models. We propose two systemic and simplified ordinary differential equation models to model the subcutaneous injection of rapid-acting insulin analogues and long-acting insulin analogues, respectively. Our models explicitly model the plasma insulin and hence have the advantage of computing the plasma insulin directly. The profiles of plasma insulin concentrations obtained from these two models are in good agreement with the experimental data. We also study the dynamics of insulin analogues, plasma insulin concentrations, and, in particular, the shape of the dynamics of plasma insulin concentrations. PMID:19292507

  14. 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.

  15. Hyaluronic acid filler injections with a 31-gauge insulin syringe.

    PubMed

    Lim, Adrian C

    2010-02-01

    Hyaluronic acid gel is a commonly used skin/soft tissue filler in cosmetic dermatology. Hyaluronic acid fillers are packaged in proprietary luer-lock syringes that can be injected via a 30-gauge, 27-gauge or larger diameter needle depending on the consistency of the gel. A method of decanting proprietary hyaluronic acid fillers into multiple 31-gauge insulin syringes for injection is described. The use of a 31-gauge insulin syringe for filler injections can potentially enhance the injection process through more accurate product delivery and placement. This has the potential to produce a more balanced and symmetrical outcome for patients. Additional benefits include less injection pain, less bleeding/bruising and higher levels of patient satisfaction.

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

    PubMed

    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.

  17. 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

  18. Enhanced bioavailability of subcutaneously injected insulin coadministered with collagen in rats and humans

    SciTech Connect

    Hori, R.; Komada, F.; Iwakawa, S.; Seino, Y.; Okumura, K. )

    1989-09-01

    The present study was undertaken to develop an agent that stabilizes insulin injected subcutaneously. {sup 125}I-Porcine insulin with 0.2 U/kg unlabeled porcine insulin was subcutaneously injected with or without collagen in the rat under the depilated skin of the back. At various times, the radioactivity in subcutaneous tissue was assayed for insulin and its metabolites by gel filtration. The degradation and absorption rate constants of insulin at the subcutaneous injection site were estimated according to a one-compartment model. The degradation rate constant of insulin in the presence of collagen at the injection site was less than half of the control rate. The inhibition was confirmed by increases in the immunoreactive insulin plasma levels and the hypoglycemic effect in rats and healthy volunteers. We postulate that collagen prevents insulin from being degraded by inhibiting proteolytic enzymes, mainly collagenase-like peptidase, in subcutaneous tissue.

  19. Enhanced bioavailability of subcutaneously injected insulin by pretreatment with ointment containing protease inhibitors

    SciTech Connect

    Takeyama, M.; Ishida, T.; Kokubu, N.; Komada, F.; Iwakawa, S.; Okumura, K.; Hori, R. )

    1991-01-01

    The present study was undertaken to develop an ointment preparation containing a protease inhibitor for stabilizing subcutaneously injected insulin. The ointment containing the protease inhibitor, gabexate mesilate or nafamostat mesilate, was applied to the skin around the insulin injection site. Three results were obtained. First, gabexate and nafamostat inhibited insulin degradation in subcutaneous tissue homogenates in vitro. Second, after application of gabexate or nafamostat ointment, an appreciable amount of gabexate or nafamostat appeared in the subcutaneous tissue of rats or hairless mice and their concentrations were comparable to those seen in the in vitro experiment. Third, insulin degradation at the subcutaneous injection site in the rat was depressed after pretreatment with gabexate or nafamostat ointment. Pretreatment with gabexate or nafamostat ointment increased the plasma immunoreactive insulin (IRI) levels and the hypoglycermic effect of insulin in healthy volunteers. These results indicate that gabexate or nafamostat ointments stabilize subcutaneously injected insulin.

  20. Effects of intracerebroventricular administration of d-fenfluramine and d-norfenfluramine, as a single injection or 2-hr infusion, on serotonin in brain: relationship to concentrations of drugs in brain.

    PubMed

    Invernizzi, R; Fracasso, C; Caccia, S; Garattini, S; Samanin, R

    1991-02-01

    The effects of d-fenfluramine (DF) and d-norfenfluramine (DNF), administered intracerebroventricularly (i.c.v.) on levels of serotonin (5-HT) in the brain, was assessed in relation to levels of drugs in brain. d-Fenfluramine, as a single injection (500 micrograms/20 microliters), caused no significant changes in 5-HT in whole brain from 15 to 480 min after injection. When infused intraventricularly for 2 hr, DF and DNF at 500 but not at 125 250 micrograms/hr, markedly reduced concentrations of 5-HT in brain 4 hr after the end of the infusion. At this time levels of DNF in brain were similar (between 4 and 5 micrograms/g) with both compounds, whereas levels of DNF after single intraventricular injections of DF were below 2 micrograms/g at all times after injection. Infusion of 500 micrograms/hr of DNF for 2-hr reduced concentrations of 5-HT in various regions of the brain, with the exception of the brainstem, whereas 250 micrograms/hr of DNF significantly lowered levels of 5-HT only in the cortex. The effect of infusion of 500 micrograms/hr of DNF was specific for 5-HT (no effect on dopamine and norepinephrine) and lasted for at least 168 hr. The results suggest that the effect on 5-HT in brain of intraventricular infusion of DF, but not a single injection, was due to the fact that, only in the former condition were adequate levels of DNF, the active metabolite of DF, reached in the brain. These results are relevant to the interpretation of studies in which biochemical changes in the brain after intraventricular administration, are reported without any measurement of the drug or its active metabolites, in plasma and brain.

  1. 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. PMID:27288705

  2. 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.

  3. Continuous subcutaneous insulin infusion versus multiple daily injections

    PubMed Central

    Karagianni, P; Sampanis, Ch; Katsoulis, Ch; Miserlis, Gr; Polyzos, S; Zografou, I; Stergiopoulos, S; Douloumbakas, I; Zamboulis, Ch

    2009-01-01

    Background and aim: Continuous Subcutaneous Insulin Infusion (CSII) and Multiple Daily insulin Injections (MDI) are both strategies aiming to achieve a tight glycemic and metabolic control. However, the choice between them remains controversial. The aim of the present study was to compare the efficacy of MDI (three or more injections daily) with CSII on glycemic control in patients with Type 1 Diabetes Mellitus and assess satisfaction from treatment in the CSII group. Material and Methods: Seventeen patients with Type 1 Diabetes Mellitus on CSII (previously on MDI) and 17 patients on MDI, matched for age, gender, BMI and duration of diabetes, were retrospectively studied. Glucosylated Hemoglobin A1c (HbA1c), frequency of hypoglycaemias (assessed as self reported episodes), BMI and total units of insulin per day were evaluated at baseline and after 6 months in both groups. CSII group completed a questionnaire concerning motive for treatment selection, advantages, deficiencies and inconvenience at the end of the study. Satisfaction from treatment was assessed with a scale from 0 to10. Results: CSII group had more hypoglycaemic episodes at baseline than MDI group (16.2±2.8 vs 2.8±1.3, p<0,001). HbA1c (8.4±0.5 before vs 7.3±0.4 after, p<0.05) and total hypoglycaemic episodes per month (16.2±2.8 before vs 8.7±2.3 after, p<0.05) significantly decreased in CSII group 6 months after baseline. On the contrary, total hypoglycaemic episodes per month were increased in MDI group (2.8±1.3 before vs 10.8 ±2,6 after, p<0.05) in order to maintain HbA1c levels. No significant differences were observed in BMI in both groups. Total insulin demands were reduced in the CSII group (49.4±3.3 before vs 39.0±4.6 after, p<0.05) and remained unchanged in MDI group. None of the patients discontinued CSII therapy, while overall satisfaction rate in this group was high. The main motive for CSII selection was frequent hypoglycaemic episodes and glucose fluctuations (10/17). The

  4. 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

  5. Intracerebroventricular injection of mu- and delta-opiate receptor antagonists block 60 Hz magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

    PubMed

    Lai, H; Carino, M

    1998-01-01

    In previous research, we have found that acute exposure to a 60 Hz magnetic field decreased cholinergic activity in the frontal cortex and hippocampus of the rat as measured by sodium-dependent high-affinity choline uptake activity. We concluded that the effect was mediated by endogenous opioids inside the brain because it could be blocked by pretreatment of rats before magnetic field exposure with the opiate antagonist naltrexone, but not by the peripheral antagonist naloxone methiodide. In the present study, the involvement of opiate receptor subtypes was investigated. Rats were pretreated by intracerebroventricular injection of the mu-opiate receptor antagonist, beta-funaltrexamine, or the delta-opiate receptor antagonist, naltrindole, before exposure to a 60 Hz magnetic field (2 mT, 1 hour). It was found that the effects of magnetic field on high-affinity choline uptake in the frontal cortex and hippocampus were blocked by the drug treatments. These data indicate that both mu- and delta-opiate receptors in the brain are involved in the magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

  6. 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

    2014-10-01

    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.

  7. Design of novel injectable cationic microspheres based on aminated gelatin for prolonged insulin action.

    PubMed

    Morimoto, Kazuhiro; Chono, Sumio; Kosai, Tadashi; Seki, Toshinobu; Tabata, Yasuhiko

    2005-07-01

    The aim of this study was to prepare two types of injectable cationized microspheres based on a native gelatin (NGMS) and aminated gelatin with ethylenediamine (CGMS) to prolong the action of insulin. Release of rhodamin B isothiocyanate insulin from CGMS was compared with that from NGMS under in-vitro and in-vivo conditions. Lower release of insulin from CGMS compared with that from NGMS was caused by the suppression of initial release. The disappearance of 125I-insulin from the injection site after intramuscular administration by NGMS and CGMS had a biphasic profile in mice. Almost all the 125I-insulin had disappeared from the injection site one day after administration by NGMS. The remaining insulin at the injection site after administration by CGMS was prolonged, with approximately 59% remaining after one day and 16% after 14 days. The disappearance of CGMS from the injection site was lower than that of NGMS. However, the difference in these disappearance rates was not great compared with those of 125I-insulin from the injection site by NGMS and CGMS. The time course of disappearance of 125I-CGMS from the injection site was similar to that of 125I-insulin by CGMS. The initial hypoglycaemic effect was observed 1 h after administration of insulin by NGMS, thereafter its effect rapidly disappeared. The hypoglycaemic effect was observed 2-4 h after administration by CGMS and continued to be exhibited for 7 days. The prolonged hypoglycaemic action by CGMS depended on the time profiles of the disappearance of insulin from muscular tissues, which occurs due to the enzymatic degradation of CGMS.

  8. 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.

  9. Effect of local insulin injection on wound vascularization in patients with diabetic foot ulcer

    PubMed Central

    ZHANG, ZHAOXIN; LV, LEI

    2016-01-01

    The aim of the present study was to investigate the effect of local insulin injection on granulation tissue formation in the wounds of patients with diabetic foot ulcer. Thirty-two patients with diabetic foot ulcer were randomly divided into an insulin (n=18) and a control (n=14) group. In the diabetic foot ulcer wound, the insulin group were administered insulin and the control group were administered an equal volume of saline. Prior to injection and at 0.5, 1.0, 2.0 and 4.0 h after injection, the fingertip blood glucose levels were determined. The growth of granulation tissue was assessed continuously for 12 days. Wound tissue was harvested at 0, 5, 7 and 12 days for the detection of CD34 expression by immunohistochemistry. The microvessel density (MVD) was calculated. No significant difference in the fasting blood glucose level was found between the two groups at any time-point (P>0.05). Growth of granulation tissue in the insulin group was more marked from 7 days after local insulin injection (24.87±0.24) and was significantly different from that in the control group (18.66±0.45) (P<0.01). New vessels were observed in the insulin group 3 days after insulin injection; however, there was no significant difference in MVD compared with the control group (P>0.05). The MVD in the insulin group increased markedly from 5 days after treatment, and the difference between the two groups was significant (P<0.01). In conclusion, local injection of insulin into the base of a diabetic foot ulcer has a significant effect on systemic blood glucose and may promote wound healing by improving the growth of granulation tissue. PMID:26893621

  10. Intracerebroventricular injection of propionic acid, an enteric metabolite implicated in autism, induces social abnormalities that do not differ between seizure-prone (FAST) and seizure-resistant (SLOW) rats.

    PubMed

    Shultz, Sandy R; Aziz, Noor A B; Yang, Li; Sun, Mujun; MacFabe, Derrick F; O'Brien, Terence J

    2015-02-01

    Autism is a complex neurodevelopmental disorder that is characterized by social abnormalities. Genetic, dietary and gut-related factors are implicated in autism, however the causal properties of these factors and how they may interact are unclear. Propionic acid (PPA) is a product of gut microbiota and a food preservative. PPA has been linked to autism, and PPA administration to rats is an animal model of the condition. Seizure-prone (FAST) and seizure-resistant (SLOW) rats were initially developed to investigate differential vulnerability to developing epilepsy. However, FAST rats also display autistic-like features, and have been proposed as a genetic model of autism. Here we examined the effects of PPA on social behavior in FAST and SLOW rats. A single intracerebroventricular injection of PPA, or phosphate-buffered saline (PBS), was administered to young-adult male FAST and SLOW rats. Immediately after treatment, rats were placed in same-treatment and same-strain pairs, and underwent social behavior testing. PPA induced social abnormalities in both FAST and SLOW rat strains. While there was no evidence of social impairment in FAST rats that were not treated with PPA, these rats were hyperactive relative to SLOW rats. Post-mortem immunofluorescence analysis of brain tissue indicated that PPA treatment resulted in increased astrogliosis in the corpus callosum and cortex compared to PBS treatment. FAST rats had increased astrogliosis in the cortex compared to SLOW rats. Together these findings support the use of PPA as a rat model of autism, but indicate there are no interactive effects between the PPA and FAST models.

  11. 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

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

    PubMed Central

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

    2015-01-01

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

  13. 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.

  14. Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics.

    PubMed

    Shao, Juntang; Zaro, Jennica L; Shen, Wei-Chiang

    2016-01-01

    Current subcutaneously (s.c.)-injected insulin (INS) products result in a hyperinsulin exposure to peripheral tissues (skeletal muscle and adipose) while INS hardly accesses to liver after injection. This unphysiological distribution raises risks of hypoglycemia episode and causes weight gain after long term treatment. An ideal INS replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. However, there are 2 factors that limit the ability of s.c. injected INS to restore the liver: peripheral gradient in INS deficient diabetes patients: (1) the transport of INS in capillary endothelium and peripheral tissues from the injection site; and (2) peripheral INS receptor (IR) mediated INS degradation. In this review, the tissue barriers against efficient liver targeting of s.c. injected INS are discussed and current advances in developing hepatoselective insulin therapeutics are introduced. PMID:27358753

  15. Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study.

    PubMed

    Tosaka, Yuka; Kanazawa, Akio; Ikeda, Fuki; Iida, Mayu; Sato, Junko; Matsumoto, Kazuhisa; Uchida, Toyoyoshi; Tamura, Yoshifumi; Ogihara, Takeshi; Mita, Tomoya; Shimizu, Tomoaki; Goto, Hiromasa; Ohmura, Chie; Fujitani, Yoshio; Watada, Hirotaka

    2015-01-01

    The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%, P = 0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL, P = 0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%, P = 0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474. PMID:26435713

  16. Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study

    PubMed Central

    Tosaka, Yuka; Kanazawa, Akio; Ikeda, Fuki; Iida, Mayu; Sato, Junko; Matsumoto, Kazuhisa; Uchida, Toyoyoshi; Tamura, Yoshifumi; Ogihara, Takeshi; Mita, Tomoya; Shimizu, Tomoaki; Goto, Hiromasa; Ohmura, Chie; Fujitani, Yoshio; Watada, Hirotaka

    2015-01-01

    The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%, P = 0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL, P = 0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%, P = 0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474. PMID:26435713

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

    PubMed

    Home, P D

    2015-11-01

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

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. Intravenously injected insulin-like growth factor (IGF) I/IGF binding protein-3 complex exerts insulin-like effects in hypophysectomized, but not in normal rats.

    PubMed

    Zapf, J; Hauri, C; Futo, E; Hussain, M; Rutishauser, J; Maack, C A; Froesch, E R

    1995-01-01

    Insulin-like growth factor (IGF) circulates in blood in two large molecular mass forms of 150 and 40 kD. Under normal conditions, most of the IGF is bound to the 150-kD complex by which it is retained in the circulation and therefore unable to exert acute insulin-like actions. The aim of this study was to answer the question whether or not IGF in the 40-kD complex is bioavailable to insulin target tissues and thus can cause acute insulin-like effects in vivo. Intravenously injected 1:1 molar recombinant human (rh) IGF I/rhIGF binding protein (BP)-3 complex lowered blood glucose and stimulated glycogen synthesis in diaphragm of hypophysectomized, but not of normal rats. The serum half-lives of the two components of the complex were similar to each other, but considerably shorter in hypox than in normal rats. On neutral gel filtration of serum both components of the injected complex appeared predominantly in the 150-kD region in normal rats. In hypox rats which lack the 150-kD complex they were found in the 40-kD region and disappeared rapidly from the circulation. We conclude that in the absence of the 150-kD complex, IGF associated with the 40-kD complex can rapidly leave the vascular compartment, reach insulin or type 1 IGF receptors and exert acute insulin-like effects. PMID:7529258

  4. Sustained Treatment with Insulin Detemir in Mice Alters Brain Activity and Locomotion

    PubMed Central

    Sartorius, Tina; Hennige, Anita M.; Fritsche, Andreas; Häring, Hans-Ulrich

    2016-01-01

    Aims Recent studies have identified unique brain effects of insulin detemir (Levemir®). Due to its pharmacologic properties, insulin detemir may reach higher concentrations in the brain than regular insulin. This might explain the observed increased brain stimulation after acute insulin detemir application but it remained unclear whether chronic insulin detemir treatment causes alterations in brain activity as a consequence of overstimulation. Methods In mice, we examined insulin detemir’s prolonged brain exposure by continuous subcutaneous (s.c.) application using either micro-osmotic pumps or daily s.c. injections and performed continuous radiotelemetric electrocorticography and locomotion recordings. Results Acute intracerebroventricular injection of insulin detemir activated cortical and locomotor activity significantly more than regular insulin in equimolar doses (0.94 and 5.63 mU in total), suggesting an enhanced acute impact on brain networks. However, given continuously s.c., insulin detemir significantly reduced cortical activity (theta: 21.3±6.1% vs. 73.0±8.1%, P<0.001) and failed to maintain locomotion, while regular insulin resulted in an increase of both parameters. Conclusions The data suggest that permanently-increased insulin detemir levels in the brain convert its hyperstimulatory effects and finally mediate impairments in brain activity and locomotion. This observation might be considered when human studies with insulin detemir are designed to target the brain in order to optimize treatment regimens. PMID:27589235

  5. Insulin

    MedlinePlus

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

  6. 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. PMID:25352633

  7. Simplified surgical placement and stabilization methods for intracerebroventricular cannulas in rat lateral ventricles.

    PubMed

    Jho, David H; Engelhard, Herbert H; Juarez, Altair; Espat, N Joseph

    2003-10-01

    Intracerebroventricular cannulation in rat models is an efficient tool for exploring the effects of substances directly injected into the CNS, bypassing the blood-brain barrier. Techniques for surgically securing the ICV cannula require a balance between ease of application and adequate stability. The authors tested several methods of lateral ventricle cannula stabilization, especially focusing on a comparison of cyanoacrylate gel to cranioplastic cement with an anchoring bone screw. PMID:15235663

  8. Safe and Efficacious Use of Automated Bolus Advisors in Individuals Treated With Multiple Daily Insulin Injection (MDI) Therapy

    PubMed Central

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

    2015-01-01

    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. PMID:25795641

  9. 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.

  10. The neuropathology of intracerebroventricular t-butylhydroperoxide.

    PubMed

    Adams, J D; Klaidman, L K; Huang, Y M; Cheng, J J; Wang, Z J; Nguyen, M; Knüsel, B; Kuda, A

    1994-06-01

    t-Butylhydroperoxide can be used as a model oxidative stress-inducing agent in the brain following intracerebroventricular administration. Mice were treated with saline, t-butanol, or t-butylhydroperoxide. t-Butanol is the major metabolite of t-butylhydroperoxide. t-Butylhydroperoxide had a number of effects, including that it damages dopaminergic, cholinergic, and GABAergic neurons as demonstrated immunohistochemically. Electron microscopic examination demonstrated that astrocytes, oligodendrocytes, endothelial cells, pericytes, and neurons are damaged by t-butylhydroperoxide. Dopamine and its metabolites were affected in a number of brain regions, as were serotonin and its metabolite. Choline acetyl transferase activity was decreased in the striatum. Edema was apparent as assessed by tissue protein levels. There was evidence of lipid peroxidation produced by t-butylhydroperoxide in the midbrain. t-Butylhydroperoxide is a neurotoxin that may be useful in understanding the unexpected ways the brain responds to oxidative stress. PMID:7916771

  11. Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues*

    PubMed Central

    Lu, Min; Sarruf, David A.; Li, Pingping; Osborn, Olivia; Sanchez-Alavez, Manuel; Talukdar, Saswata; Chen, Ai; Bandyopadhyay, Gautam; Xu, Jianfeng; Morinaga, Hidetaka; Dines, Kevin; Watkins, Steven; Kaiyala, Karl; Schwartz, Michael W.; Olefsky, Jerrold M.

    2013-01-01

    Sirt1 is a NAD+-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1f/f mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet. PMID:23457303

  12. Switching from subcutaneous insulin injection to oral vildagliptin administration in hemodialysis patients with type 2 diabetes: a pilot study.

    PubMed

    Yoshida, Naoshi; Babazono, Tetsuya; Hanai, Ko; Uchigata, Yasuko

    2016-08-01

    We conducted this pilot study to examine efficacy and safety of switching from subcutaneous injection of insulin to oral administration of a DPP-4 inhibitor, vildagliptin, in type 2 diabetic patients undergoing hemodialysis. Consecutive type 2 diabetic patients on hemodialysis who were switched from insulin to vildagliptin between August 2010 and April 2011 were extracted from the hospital database. In patients whose post-switch increase in glycated albumin (GA) levels was <1.5 % without resuming insulin at least 24 weeks, the switch was defined as efficacious. In patients who resumed insulin therapy due to worsening of glycemic control or in patients whose GA levels increased by 1.5 % or more, the switch was considered inefficacious. To predict patients in whom switch to vildagliptin proved efficacious, receiver-operating characteristic (ROC) analysis and logistic regression analysis were performed. A total of 20 patients were extracted; insulin dose was 12 ± 4 units/day; levels of GA and HbA1c was 21.0 ± 3.7 % and 6.5 ± 0.6 %, respectively. Among them, 11 patients were efficaciously switched to vildagliptin. ROC analysis and logistic analysis showed that patients with a shorter duration of diabetes, as well as lower levels of GA and HbA1c, appeared to have a higher likelihood of successful treatment switches. None of the patients developed hypoglycemic symptoms, ketoacidosis, or serious adverse events. In conclusion, efficacious change from insulin to vildagliptin was possible in approximately a half of type 2 diabetic dialysis patients. Long-term follow-up studies including large number of patients are needed to confirm these results. PMID:27193434

  13. 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.

  14. Lipodystrophy in Insulin-Treated Subjects and Other Injection-Site Skin Reactions: Are We Sure Everything is Clear?

    PubMed

    Gentile, Sandro; Strollo, Felice; Ceriello, Antonio

    2016-09-01

    Physicians and patients have long been aware of skin lesions at the sites of insulin injections, referred to as lipodystrophy that can present as lipoatrophy (LA) or lipohypertrophy (LH). However, the reported prevalence of these different skin lesions varies widely, emphasizing the need for a correct identification method. In this short review we discuss LA and LH and also take into account other skin lesions, such as bruising, as well as different needle injuries, including those associated with the subcutaneous injection of pegvisomant (a drug aimed at counteracting the high levels of growth hormone associated with acromegaly), long-acting exenatide (a glucagon-like peptide-1 receptor agonist), and anti-tumor necrosis factor-alpha biologic agents (used against Crohn's disease). In these latter cases specific studies are warranted to understand the pathophysiological background and possible prevention. However, the most common lesion is still insulin injection site-related LD, so a strong effort has to be made to avoid the confusion generated by previously misleading classifications which were barely able to reliably distinguish between LA and LH.

  15. Lipodystrophy in Insulin-Treated Subjects and Other Injection-Site Skin Reactions: Are We Sure Everything is Clear?

    PubMed

    Gentile, Sandro; Strollo, Felice; Ceriello, Antonio

    2016-09-01

    Physicians and patients have long been aware of skin lesions at the sites of insulin injections, referred to as lipodystrophy that can present as lipoatrophy (LA) or lipohypertrophy (LH). However, the reported prevalence of these different skin lesions varies widely, emphasizing the need for a correct identification method. In this short review we discuss LA and LH and also take into account other skin lesions, such as bruising, as well as different needle injuries, including those associated with the subcutaneous injection of pegvisomant (a drug aimed at counteracting the high levels of growth hormone associated with acromegaly), long-acting exenatide (a glucagon-like peptide-1 receptor agonist), and anti-tumor necrosis factor-alpha biologic agents (used against Crohn's disease). In these latter cases specific studies are warranted to understand the pathophysiological background and possible prevention. However, the most common lesion is still insulin injection site-related LD, so a strong effort has to be made to avoid the confusion generated by previously misleading classifications which were barely able to reliably distinguish between LA and LH. PMID:27456528

  16. 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.

  17. Phenylboronic Acid Appended Pyrene-Based Low-Molecular-Weight Injectable Hydrogel: Glucose-Stimulated Insulin Release.

    PubMed

    Mandal, Deep; Mandal, Subhra Kanti; Ghosh, Moumita; Das, Prasanta Kumar

    2015-08-17

    A pyrene-containing phenylboronic acid (PBA) functionalized low-molecular-weight hydrogelator was synthesized with the aim to develop glucose-sensitive insulin release. The gelator showed the solvent imbibing ability in aqueous buffer solutions of pH values, ranging from 8-12, whereas the sodium salt of the gelator formed a hydrogel at physiological pH 7.4 with a minimum gelation concentration (MGC) of 5 mg mL(-1) . The aggregation behavior of this thermoreversible hydrogel was studied by using microscopic and spectroscopic techniques, including transmission electron microscopy, FTIR, UV/Vis, luminescence, and CD spectroscopy. These investigations revealed that hydrogen bonding, π-π stacking, and van der Waals interactions are the key factors for the self-assembled gelation. The diol-sensitive PBA part and the pyrene unit in the gelator were judiciously used in fluorimetric sensing of minute amounts of glucose at physiological pH. The morphological change of the gel due to addition of glucose was investigated by scanning electron microscopy, which denoted the glucose-responsive swelling of the hydrogel. A rheological study indicated the loss of the rigidity of the native gel in the presence of glucose. Hence, the glucose-induced swelling of the hydrogel was exploited in the controlled release of insulin from the hydrogel. The insulin-loaded hydrogel showed thixotropic self-recovery property, which hoisted it as an injectable soft composite. Encouragingly, the gelator was found to be compatible with HeLa cells.

  18. 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

  19. Deleterious effects of lard-enriched diet on tissues fatty acids composition and hypothalamic insulin actions.

    PubMed

    Dornellas, A P S; Watanabe, R L H; Pimentel, G D; Boldarine, V T; Nascimento, C M O; Oyama, L M; Ghebremeskel, K; Wang, Y; Bueno, A A; Ribeiro, E B

    2015-12-01

    Altered tissue fatty acid (FA) composition may affect mechanisms involved in the control of energy homeostasis, including central insulin actions. In rats fed either standard chow or a lard-enriched chow (high in saturated/low in polyunsaturated FA, HS-LP) for eight weeks, we examined the FA composition of blood, hypothalamus, liver, and retroperitoneal, epididymal and mesenteric adipose tissues. Insulin-induced hypophagia and hypothalamic signaling were evaluated after intracerebroventricular insulin injection. HS-LP feeding increased saturated FA content in adipose tissues and serum while it decreased polyunsaturated FA content of adipose tissues, serum, and liver. Hypothalamic C20:5n-3 and C20:3n-6 contents increased while monounsaturated FA content decreased. HS-LP rats showed hyperglycemia, impaired insulin-induced hypophagia and hypothalamic insulin signaling. The results showed that, upon HS-LP feeding, peripheral tissues underwent potentially deleterious alterations in their FA composition, whist the hypothalamus was relatively preserved. However, hypothalamic insulin signaling and hypophagia were drastically impaired. These findings suggest that impairment of hypothalamic insulin actions by HS-LP feeding was not related to tissue FA composition. PMID:26525379

  20. A physiological increase of insulin in the olfactory bulb decreases detection of a learned aversive odor and abolishes food odor-induced sniffing behavior in rats.

    PubMed

    Aimé, Pascaline; Hegoburu, Chloé; Jaillard, Tristan; Degletagne, Cyril; Garcia, Samuel; Messaoudi, Belkacem; Thevenet, Marc; Lorsignol, Anne; Duchamp, Claude; Mouly, Anne-Marie; Julliard, Andrée Karyn

    2012-01-01

    Insulin is involved in multiple regulatory mechanisms, including body weight and food intake, and plays a critical role in metabolic disorders such as obesity and diabetes. An increasing body of evidence indicates that insulin is also involved in the modulation of olfactory function. The olfactory bulb (OB) contains the highest level of insulin and insulin receptors (IRs) in the brain. However, a role for insulin in odor detection and sniffing behavior remains to be elucidated. Using a behavioral paradigm based on conditioned olfactory aversion (COA) to isoamyl-acetate odor, we demonstrated that an intracerebroventricular (ICV) injection of 14 mU insulin acutely decreased olfactory detection of fasted rats to the level observed in satiated animals. In addition, whereas fasted animals demonstrated an increase in respiratory frequency upon food odor detection, this effect was absent in fasted animals receiving a 14 mU insulin ICV injection as well as in satiated animals. In parallel, we showed that the OB and plasma insulin levels were increased in satiated rats compared to fasted rats, and that a 14 mU insulin ICV injection elevated the OB insulin level of fasted rats to that of satiated rats. We further quantified insulin receptors (IRs) distribution and showed that IRs are preferentially expressed in the caudal and lateral parts of the main OB, with the highest labeling found in the mitral cells, the main OB projection neurons. Together, these data suggest that insulin acts on the OB network to modulate olfactory processing and demonstrate that olfactory function is under the control of signals involved in energy homeostasis regulation and feeding behaviors. PMID:23251461

  1. Switching to Multiple Daily Insulin Injections in Children and Adolescents with Type 1 Diabetes: Revisiting Benefits from Oman

    PubMed Central

    Sharef, Sharef Waadallah; Ullah, Irfan; Al-Shidhani, Azza; Al-Farsi, Tariq; Al-Yaarubi, Saif

    2015-01-01

    Objectives Optimal glycemic control is an important goal in the management of type 1 diabetes mellitus (T1DM). Although the use of multiple daily injections (MDI) is a common regimen worldwide, its use is not yet universal in many countries. Our aim was to evaluate the effects of switching from a twice daily (BID) to a MDI insulin regimen in children and adolescents with T1DM in order to revisit its benefits in the Omani population. Methods We conducted a retrospective cohort study of children and adolescents with T1DM at Sultan Qaboos University Hospital, Muscat, Oman, between January 2007 and June 2013. Patients using the BID regimen for more than six months who were then switched to MDI were included in the analysis. We compared glycated hemoglobin levels (HbA1c) before and after the regimen change. Results Fifty-three children were eligible for the study. Ten patients were excluded for various reasons. The remaining 43 patients were 58% male and 42% female, with a mean age of 9.4±3.7 years. There was significant decrease in the overall mean HbA1c level from baseline (10.0) compared to three months after switching to MDI (9.5); p=0.023. Nevertheless, the improvement was not significant in the subsequent follow-up visits at six and nine months. The reduction in HbA1c values was observed mainly in children five to 11 years. Conclusions Switching from a BID to MDI insulin regimen has favorable effects on the overall control of T1DM in children and adolescents, as assessed by HbA1c levels. In addition, this regimen has been proved to be safe and well tolerated by patients. PMID:25960831

  2. Insulin pump use in young children in the T1D Exchange clinic registry is associated with lower hemoglobin A1c levels than injection therapy.

    PubMed

    Blackman, Scott M; Raghinaru, Dan; Adi, Saleh; Simmons, Jill H; Ebner-Lyon, Laurie; Chase, H Peter; Tamborlane, William V; Schatz, Desmond A; Block, Jennifer M; Litton, Jean C; Raman, Vandana; Foster, Nicole C; Kollman, Craig R; DuBose, Stephanie N; Miller, Kellee M; Beck, Roy W; DiMeglio, Linda A

    2014-12-01

    Insulin delivery via injection and continuous subcutaneous insulin infusion (CSII) via insulin pump were compared in a cross-sectional study (n = 669) and retrospective longitudinal study (n = 1904) of young children (<6 yr) with type 1 diabetes (T1D) participating in the T1D Exchange clinic registry. Use of CSII correlated with longer T1D duration (p < 0.001), higher parental education (p < 0.001), and annual household income (p < 0.006) but not with race/ethnicity. Wide variation in pump use was observed among T1D Exchange centers even after adjusting for these factors, suggesting that prescriber preference is a substantial determinant of CSII use. Hemoglobin A1c (HbA1c) was lower in pump vs. injection users (7.9 vs. 8.5%, adjusted p < 0.001) in the cross-sectional study. In the longitudinal study, HbA1c decreased after initiation of CSII by 0.2%, on average (p < 0.001). Frequency of a severe hypoglycemia (SH) event did not differ in pump vs. injection users (p = 0.2). Frequency of ≥1 parent-reported diabetic ketoacidosis (DKA) event in the prior year was greater in pump users than injection users (10 vs. 8%, p = 0.04). No differences between pump and injection users were observed for clinic-reported DKA events. Children below 6 yr have many unique metabolic characteristics, feeding behaviors, and care needs compared with older children and adolescents. These data support the use of insulin pumps in this youngest age group, and suggest that metabolic control may be improved without increasing the frequency of SH, but care should be taken as to the possibly increased risk of DKA. PMID:24494980

  3. 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.

  4. 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. PMID:27454282

  5. 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

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

    PubMed

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

    2016-06-01

    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

  7. 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

  8. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

    PubMed

    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. PMID:27511839

  9. [Inhaled insulin, new perspective for insulin therapy].

    PubMed

    Radermecker, R P; Sélam, J L

    2005-01-01

    Since the discovery of insulin and its use in diabetes care, patients, physicians and nurses dream of another way of insulin administration than the subcutaneous injections actually used. Different types of insulin administration have been evaluated and, particularly, that using the pulmonary route. The use of this alternative method to deliver insulin may result in improved patient compliance, facilitate intensified therapies and avoid the delay of initiating insulin administration because patient's reluctance. The different insulin pulmonary delivering devices actually studied will be presented. Preliminary data comparing this way of administration and the subcutaneous injection of human regular insulin are good, but sufficient data comparing inhaled insulin with the new short-acting insulin analogues are not yet available. Among various difficulties of the pulmonary insulin delivery, the finding of an effective promoter, capable of increasing the bioavailability of insulin, is a crucial issue. The cost of such insulin administration might also be a problem. Finally, careful studies concerning the safety of this kind of administration, particularly potential long-term pulmonary toxicity, are mandatory. Nevertheless, inhaled insulin is an attractive topic in which most important pharmaceutical companies are currently involved.

  10. Pre-training Catechin gavage prevents memory impairment induced by intracerebroventricular streptozotocin in rats

    PubMed Central

    Zamani, Marzieh; Rohampour, Kambiz; Zeraati, Maryam; Hosseinmardi, Narges; Kazemian, Mostafa M.

    2015-01-01

    Objective: To evaluate the effects of Catechin (CAT) on memory acquisition and retrieval in the animal model of sporadic alzheimer’s disease (sAD) induced by intracerebroventricular (icv) injection of streptozotocin (STZ) in passive avoidance memory test. Methods: Thirty adult rats were divided into 5 experimental groups (n=6). Animals were treated by icv saline/STZ (3 mg/kg) injection at day one and 3 after cannulation. The STZ+CAT group received 40 mg/kg CAT by daily gavages for 10 days, after icv STZ treatment and before training. The step-through latency (STL) and time spent in the dark compartment (TDC) were evaluated to examine the memory acquisition and retrieval. All tests were performed in Qom University of Medical Sciences, Qom, Iran, from April to December 2013. Results: The STZ treatment significantly decreased STL and increased the number of entries to the dark compartment on the training day. It also increased TDC, on day one and 7 after training. Pre-training gavage of CAT reversed the STL significantly (p=0.027). The CAT treatment also decreased the TDC in both early and late retrieval, in respect to STZ group. Conclusion: This data suggests that CAT as an antioxidant could improve both memory acquisition and retrieval in the animal model of sAD. PMID:26166589

  11. Efficacy of anti-Abeta antibody isotypes used for intracerebroventricular immunization in TgCRND8.

    PubMed

    Chauhan, Neelima B; Siegel, George J

    2005-03-01

    We have previously demonstrated that intracerebroventricular (ICV) injection of anti-Abeta (IgG1, kappa against the 1-28 region of Abeta) reduced cerebral amyloid plaques by 50% after 1 month without producing hemorrhage or activating IL-1beta responses in Tg2576 brain [N.B. Chauhan, G.J. Siegel, Reversal of amyloid beta toxicity in Alzheimer's disease model Tg2576 by intraventricular antiamyloid beta antibody, J. Neurosci. Res. 69 (1) (2002) 10-23]. The current report compares the efficacy of IgG1, IgG2a and IgG2b isotypes of anti-Abeta against several different epitopes of Abeta in clearing cerebral Abeta after a single bolus ICV injection in TgCRND8. Consistent with earlier in vitro findings from other laboratories, these in vivo data demonstrate that all IgG1 isotype antibodies tested cleared cerebral Abeta more efficiently than did IgG2a and IgG2b antibodies without producing histotoxicity in brain, liver or kidney, while an antibody against the C-terminus of Abeta did not reduce plaques or diminish their accumulation with aging of the animals. Intriguingly, there was no significant difference between the Abeta-reducing efficiency of IgG1 anti-Abeta antibodies directed against residues 3-6, against residues 1-10 or against residues 1-28 of N-terminus Abeta.

  12. Very High Plasma Concentrations of a Monoclonal Antibody against the Human Insulin Receptor Are Produced by Subcutaneous Injection in the Rhesus Monkey.

    PubMed

    Boado, Ruben J; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang; Pardridge, William M

    2016-09-01

    Brain penetration of recombinant protein drugs is possible following the re-engineering of the drug as an IgG fusion protein. The IgG domain is a monoclonal antibody (mAb) against an endogenous blood-brain barrier (BBB) receptor transporter, such as the insulin receptor. One such mAb targets the human insulin receptor (HIR) and is active in Rhesus monkeys. Prior work has measured the plasma pharmacokinetics of HIRMAb-derived fusion proteins following intravenous (IV) infusion. However, an alternative method of administration for chronic treatment of brain disease is the subcutaneous (SQ) route. The extent to which an antibody against the insulin receptor undergoes systemic distribution and clearance is unknown. Therefore, in the present study, the rate of plasma clearance of the HIRMAb is measured in Rhesus monkeys following IV or SQ administration of 3, 10, and 30 mg/kg doses of the antibody. The HIRMAb is readily absorbed into the systemic circulation following SQ injection with a 42% plasma bioavailability. The rate of plasma clearance of the antibody, 0.04-0.06 mL/min/kg, is the same following either IV or SQ administration. Owing to the slow rate of plasma clearance of the antibody, high concentrations of the HIRMAb are sustained in plasma for days after the SQ injection. The plasma concentration of the HIRMAb exceeds 0.8 mg/mL, which is 9% of the entire plasma IgG pool in the primate, after the SQ injection of the high dose, 30 mg/kg, of the antibody. In summary, the pharmacokinetics of plasma clearance of the HIRMAb are such that HIRMAb-derived fusion proteins can be developed as protein therapeutics for the brain with chronic SQ administration on a weekly or twice-weekly regimen. PMID:27513815

  13. Insulin-derived amyloidosis

    PubMed Central

    Gupta, Yashdeep; Singla, Gaurav; Singla, Rajiv

    2015-01-01

    Amyloidosis is the term for diseases caused by the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. Insulin-derived amyloidosis is a rare, yet significant complication of insulin therapy. Insulin-derived amyloidosis at injection site can cause poor glycemic control and increased insulin dose requirements because of the impairment in insulin absorption, which reverse on change of injection site and/or excision of the mass. This entity should be considered and assessed by histopathology and immunohistochemistry, in patients with firm/hard local site reactions, which do not regress after cessation of insulin injection at the affected site. Search strategy: PubMed was searched with terms “insulin amyloidosis”. Full text of articles available in English was reviewed. Relevant cross references were also reviewed. Last search was made on October 15, 2014. PMID:25593849

  14. 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. PMID:27083302

  15. Clinical utility of insulin and insulin analogs

    PubMed Central

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

    2013-01-01

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

  16. 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. Cardiovascular effects of histamine administered intracerebroventricularly in critical haemorrhagic hypotension in rats.

    PubMed

    Jochem, J

    2000-06-01

    The study was designed to determine the cardiovascular effects of histamine administered intracerebroventricularly (icv) in a rat model of volume-controlled haemorrhagic shock. The withdrawal of approximately 50% of total blood volume resulted in the death of all control saline icv treated animals within 30 min. Icv injection of histamine produced a prompt dose-dependent (0.1-100 nmol) and long-lasting (10-100 nmol) increase in mean arterial pressure (MAP), pulse pressure (PP) and heart rate (HR), with a 100% survival of 2h after treatment (100 nmol). The increase in MAP and HR after histamine administration in bled rats in comparison to the normovolaemic animals was 2.7-3.3- and 1.3-3.6-fold higher, respectively. Pretreatment with chlorpheniramine (50 nmol icv), H1 receptor antagonist, inhibited the increase in MAP, PP, HR and survival rate produced by histamine, while chlorpheniramine given alone had no effect. Neither ranitidine (50 nmol icv), H2 histamine receptor antagonist, nor thioperamide (50 nmol icv), H3 receptor blocker, influenced the histamine action, however, when given alone, both evoked the pressor effect with elongation of survival time. It can be concluded that histamine administered icv reverses the haemorrhagic shock conditions, and histamine H1 receptors are involved.

  18. Intracerebroventricular Administration of Mineralocorticoid Receptor Antisense Oligonucleotides Attenuates Salt Appetite in the Rat.

    PubMed

    Ma; Itharat; Fluharty; Sakai

    1997-10-01

    The anterior ventral third ventricle (AV3V) region of the brain contains high concentrations of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that are important in the maintenance of body fluid and electrolyte balance as well as other physiological processes. Daily intracerebroventricular pulse injections of MR antisense oligonucleotides significantly suppressed deoxycorticosterone acetate (DOCA) induced salt appetite in a dose-related manner. Similar administration of GR antisense or scrambled/sense oligonucleotide into the third ventricle failed to inhibit salt appetite. Salt appetite aroused after adrenalectomy was not suppressed by MR antisense oligonucleotide treatments but was suppressed by an antisense oligonucleotide directed against the angiotensin II AT1 receptor subtype. Receptor binding analysis demonstrated that MR and GR oligonucleotide treatments each reduced their respective receptor subtypes. Finally, although GR antisense oligonucleotide treatment was ineffective in suppressing DOCA-induced salt appetite, this treatment did increase stress induced corticosterone release as well as delayed the recovery of corticosterone to basal levels after stress. PMID:9787254

  19. Insulin C-peptide test

    MedlinePlus

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

  20. 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

  1. [Local lipohypertrophy in insulin treatment].

    PubMed

    Herold, D A; Albrecht, G

    1993-01-01

    Local lipoatrophy and lipohypertrophy at injection sites are well known side effects of treatment with insulin. Conditions favouring these local complications are created when repeated or continuous injections are given into the same areas. We report on a 27-year-old female patient who suffered from persistent local swellings after use of an external pump which continuously injected human insulin via indwelling cannulas.

  2. Concentrated insulins: the new basal insulins

    PubMed Central

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

    2016-01-01

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

  3. Intracerebroventricular porcine corticotropin-releasing hormone and cortisol effects on pig immune measures and behavior.

    PubMed

    Salak-Johnson, J L; McGlone, J J; Whisnant, C S; Norman, R L; Kraeling, R R

    1997-01-01

    The effects of intracerebroventricular (icv) administration of porcine corticotropin-releasing hormone (pCRH) and cortisol on the immune system and behavior were examined in domestic pigs. In Experiment 1, 50 micrograms of pCRH in 200 microliters of saline or 200 microliters of vehicle was administered i.c.v. at 0600 h. Blood samples were obtained at 0600 (prior to injection), 0700, and 0800 h. Plasma cortisol concentrations were higher at 1 and 2 h after pCRH than after saline. Generally, pCRH failed to effect NK cytotoxicity or lymphocyte proliferation in response to phytohemagluttin (PHA). However, 1 h postinjection, pigs administered pCRH i.c.v. had marginally lower NK activity than control pigs. Pigs injected with pCRH had substantially lower neutrophil chemotaxis (CHTX) than the control pigs at 1 and 2 h postinjection. As blood cortisol concentration increased, neutrophil CHTX decreased. Pigs injected i.c.v. with pCRH had higher neutrophil numbers and neutrophil:lymphocyte ratios than control pigs. Percentage of lymphocytes was higher among control than treated pigs. Central pCRH increased overall activity, particularly walking, standing, licking, rooting, and increased activity-related sequences (e.g., sit, walk and stand, walk), but reduced complex oral/nasal sequences (e.g., root, lick). In Experiment 2, pigs were injected i.c.v. with 10 micrograms of cortisol in 200 microliters of saline or with vehicle at 0600 h. Administration of cortisol failed to effect NK cytotoxicity, lymphocyte proliferation, CHTX, or leukocyte distribution. Pigs given cortisol had no apparent change in behavior. These data indicate leukocyte distribution and specific neutrophil function in pigs were significantly modulated by stress-related hormones of the hypothalamic-pituitary-adrenal axis and complexity of behavioral sequences (pigs repeating certain behavioral sequences) associated with increased activity was reduced. Oral/nasal stereotypies (as seen among confined sows) were

  4. Insulin pumps.

    PubMed

    Pickup, J

    2010-02-01

    Insulin pump therapy is now more than 30 years old, and is an established part of the routine care of selected people with type 1 diabetes. Nevertheless, there are still significant areas of concern, particularly how pumps compare with modern injection therapy, whether the increasingly sophisticated pump technologies like onboard calculators and facility for computer download offer any real benefit, and whether we have a consensus on the clinical indications. The following papers offer some insight into these and other current questions.

  5. Insulin pump therapy in pregnancy.

    PubMed

    Kesavadev, Jothydev

    2016-09-01

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

  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. 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

  8. Diabetic lipohypertrophy delays insulin absorption.

    PubMed

    Young, R J; Hannan, W J; Frier, B M; Steel, J M; Duncan, L J

    1984-01-01

    The effect of lipohypertrophy at injection sites on insulin absorption has been studied in 12 insulin-dependent diabetic patients. The clearance of 125I-insulin from sites with lipohypertrophy was significantly slower than from complementary nonhypertrophied sites (% clearance in 3 h, 43.8 +/- 3.5 +/- SEM) control; 35.3 +/- 3.9 lipohypertrophy, P less than 0.05). The degree of the effect was variable but sufficient in several patients to be of clinical importance. Injection-site lipohypertrophy is another factor that modifies the absorption of subcutaneously injected insulin.

  9. 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.

  10. Insulin-resistant brain state: the culprit in sporadic Alzheimer's disease?

    PubMed

    Correia, Sónia C; Santos, Renato X; Perry, George; Zhu, Xiongwei; Moreira, Paula I; Smith, Mark A

    2011-04-01

    Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease (sAD) pathology. Indeed, the "insulin-resistant brain state" has been hypothesized to form the core of the neurodegenerative events that occur in sAD. In this vein, intracerebroventricular administration of subdiabetogenic doses of streptozotocin (STZ) in rats can induce an insulin-resistant brain state, which is proposed as a suitable experimental model of sAD. This review highlights the involvement of disturbed brain insulin metabolism in sAD etiopathogenesis. Furthermore, current knowledge demonstrates that central STZ administration produces brain pathology and behavioral changes that resemble changes found in sAD patients. The STZ-intracerebroventricularly treated rat represents a promising experimental tool in this field by providing new insights concerning early brain alterations in sAD, which can be translated in novel etiopathogenic and therapeutic approaches in this disease.

  11. Stimulation of luteinizing hormone subunit gene expression by pulsatile intracerebroventricular microinjection of galanin in female rats.

    PubMed

    Gajewska, A; Zwierzchowski, L; Kochman, K

    2004-06-01

    Although galanin, which exerts its effects both at the hypothalamic and pituitary level, has been implicated as an important neuroendocrine regulator of hypothalamic-pituitary-gonadal axis activity, there is a lack of data concerning its involvement in the regulation of gonadotropin subunit gene expression. To elucidate whether galanin can influence luteinizing hormone (LH) subunit mRNA content, as well as affect gonadotropin-releasing hormone (GnRH) receptor activity, a model based on pulsatile (one pulse per hour over 5 h) galanin (1 nM) microinjections directly into the third cerebral ventricle of ovariectomized (OVX) and/or oestrogen/progesterone-pretreated rats was used. Furthermore, to determine galanin effects on GnRH-induced LH subunit mRNA synthesis, a cocktail of 1 nM GnRH and 1 nM galanin was coadministered in a pulsatile manner to OVX/steroid primed rats. Subsequently, to obtain data concerning the role of galanin receptors in the regulation of pituitary alpha (common to LH, follicle-stimulating hormone, thyroid-stimulating hormone) and LHbeta subunit gene expression, OVX/oestrogen/progesterone rats received microinjections of 1 nM of the receptor antagonist galantide and 1 nM of galanin. In this case, both substances were administered separately, with a 30 min lag, according to which each galantide pulse always preceded a galanin pulse. Northern-blot analysis revealed that intracerebroventricular pulsatile galanin injections were effective in stimulation of both alpha and LHbeta subunit mRNA levels and that this effect was apparently steroid-dependent. Moreover, galanin also up-regulated GnRH receptor functional parameters (affinity and maximum binding capacity) but was ineffective in potentiating GnRH-induced accumulation of both subunit mRNAs. The results from the study also indicate that galanin acts through its own receptor(s) because a receptor antagonist, galantide, significantly reduced the stimulatory effect exerted by galanin on the expression

  12. [Alleged suicide by insulin].

    PubMed

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

    2015-01-01

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

  13. The role of oestradiol in sexually dimorphic hypothalamic-pituitary-adrena axis responses to intracerebroventricular ethanol administration in the rat.

    PubMed

    Larkin, J W; Binks, S L; Li, Y; Selvage, D

    2010-01-01

    Systemic ethanol (EtOH) administration activates the hypothalamic-pituitary-adrenal (HPA) axis of rats in a sexually dimorphic manner. The present studies tested the role played by the central nervous system (CNS) in this phenomenon. To localise the effects of the drug to the brain, we utilised an experimental paradigm whereby a small, nontoxic amount of the drug was delivered via intracerebroventricular (i.c.v.) injection. EtoH administered i.c.v. rapidly diffuses throughout the cerebrospinal fluid and brain, and does not cause neuronal damage or have any long-term physiological or behavioural effects. Experimental groups included intact males, intact cycling females, and ovariectomised (OVX) animals with or without replacement oestradiol (E(2)). Intracerebroventricular EtOH-induced HPA hormonal activation was determined by measuring plasma adrenocorticotrophin (ACTH) levels. Activation of brain areas that both regulate HPA function and are responsive to gonadal hormones was determined using expression of the transcription factor c-fos (Fos) as a marker of neuronal activity. We observed sex- and oestrous cycle- dependent differences in HPA activation by EtOH as measured by both these parameters. ACTH secretion was highest in females in pro-oestrus or oestrus, just prior to or after the endogenous peak of E(2), as was Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coreuleus (LC) of the brainstem. In OVX animals, E(2) replacement caused an increase in PVN and LC Fos expression in response to i.c.v. EtOH compared to OVX controls, but a decrease in ACTH secretion. Taken together, these results indicate that at the level of the CNS, EtOH stimulates HPA activity more robustly at times when the effects of E(2) are high, but that E(2) alone is not responsible for this effect. The data further suggest that the LC plays an important role in the circuitry, which appears to be different from that activated following the systemic

  14. Effect of intracerebroventricular administration of angiotensin II on emetic reflex in dogs.

    PubMed

    Gupta, Y K; Chugh, A; Bhandari, P; Seth, S D

    1989-06-01

    Area postrema is rich in angiotensin II receptors and intravenous (iv) administration of angiotensin II has been reported to elicit emesis. However, in the present study intracerebroventricular (icv) administration of angiotensin II up to a dose of 10 micrograms failed to elicit emesis. It is suggested that presence of a cerebrospinal fluid-brain barrier in area postrema most probably prevents access of icv angiotensin II to its receptors which are otherwise accessible on iv administration. PMID:2583747

  15. Oral Insulin and Buccal Insulin: A Critical Reappraisal

    PubMed Central

    Heinemann, Lutz; Jacques, Yves

    2009-01-01

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

  16. 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

  17. 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.

  18. 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...

  19. New Insulin Delivery Recommendations.

    PubMed

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

    2016-09-01

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

  20. New Insulin Delivery Recommendations.

    PubMed

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

    2016-09-01

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

  1. Inhibition of insulin amyloid fibril formation by cyclodextrins.

    PubMed

    Kitagawa, Keisuke; Misumi, Yohei; Ueda, Mitsuharu; Hayashi, Yuya; Tasaki, Masayoshi; Obayashi, Konen; Yamashita, Taro; Jono, Hirofumi; Arima, Hidetoshi; Ando, Yukio

    2015-01-01

    Localized insulin-derived amyloid masses occasionally form at the site of repeated insulin injections in patients with insulin-dependent diabetes and cause subcutaneous insulin resistance. Various kinds of insulin including porcine insulin, human insulin, and insulin analogues reportedly formed amyloid fibrils in vitro and in vivo, but the impact of the amino acid replacement in insulin molecules on amyloidogenicity is largely unknown. In the present study, we demonstrated the difference in amyloid fibril formation kinetics of human insulin and insulin analogues, which suggests an important role of the C-terminal domain of the insulin B chain in nuclear formation of amyloid fibrils. Furthermore, we determined that cyclodextrins, which are widely used as drug carriers in the pharmaceutical field, had an inhibitory effect on the nuclear formation of insulin amyloid fibrils. These findings have significant implications for the mechanism underlying insulin amyloid fibril formation and for developing optimal additives to prevent this subcutaneous adverse effect.

  2. [Insulin-induced lipohypertrophy treated by liposuction].

    PubMed

    Brun, A; Comparin, J-P; Voulliaume, D; Chekaroua, K; Foyatier, J-L; Perrot, P

    2007-06-01

    The incidence of insulin-dependent diabetes mellitus increase permanently, with early diagnosis. Insulin is the treatment of this pathology. Insulin therapy is associated with complication such as lipodystrophies at injection sites leading functional and aesthetics disorders (pain, reduction of treatment efficiency, haematomas and oedemas). Our report two cases to illustrate the effectiveness of the suction-assisted lipectomy (SAL) on these lipodystrophies. We present two cases of insulin dependent diabetics patients with lipodystrophies of thighs, abdomen, and shoulders treated by SAL. The various analyzed parameters are: aesthetic aspect, efficiency of insulin treatment, ease injection, and pain reduction. We observe a significant reduction of insulin dose necessary to obtain a normoglycemia half time. This treatment allow a better control of pain, control of haematomas and oedemas at the injection sites and an aesthetic improvement. The lipoaspiration is thus a simple and effective treatment of lipodystrophies due to insulin.

  3. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine

    PubMed Central

    Belhekar, Mahesh N.; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  4. A case of hypersensitivity to soluble and isophane insulins but not to insulin glargine.

    PubMed

    Belhekar, Mahesh N; Pai, Sarayu; Tayade, Parimal; Dalwadi, Pradip; Munshi, Renuka; Varthakavi, Prema

    2015-01-01

    Insulin is an important agent for the treatment of diabetes mellitus (DM). Allergic reactions to insulin therapy, although rare, have been evident since animal insulin became available for the treatment of DM in 1922. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. Here, we present a case of Type 2 DM who demonstrated immediate (Type 1) hypersensitivity reaction on the sites of subcutaneous injection of soluble and isophane insulin but insulin glargine was tolerated well and provided good glycemic control. PMID:25878390

  5. The differential profiles of withdrawal symptoms induced by morphine and beta-endorphin administered intracerebroventricularly in mice.

    PubMed

    Park, S-H; Sim, Y-B; Kang, Y-J; Kim, C-H; Kwon, M-S; Suh, H-W

    2012-08-30

    In the present study, withdrawal symptoms induced by morphine or β-endorphin administered intracerebroventricularly (i.c.v.) were compared in ICR mice. Naloxone (10mg/kg) was post-treated intraperitoneally (i.p.) 3h after either a single or repeated (1 time/day for 3 days) i.c.v. injections with opioids. Withdrawal symptoms such as jumping frequency, diarrhea, weight loss, rearing, penile licking and paw tremor were observed for 30 min immediately after naloxone treatment. Withdrawal symptoms (jumping, diarrhea, weight loss, rearing, penile licking and paw tremor) observed in the group treated with morphine was persistently increased during 3 days. On the other hand, withdrawal symptoms such as diarrhea, weight loss and rearing in β-endorphin-treated group were increased after a single injection with β-endorphin, but gradually decreased after the repeated injection. Furthermore, no jumping behavior, penile licking and paw tremor in β-endorphin-treated group were observed throughout the whole period of time. In addition, the hypothalamic changes of several signal molecules such as pERK, pCaMK-IIα, c-FOS and pCREB expression were observed during the presence or absence of withdrawal responses induced by morphine or β-endorphin administered once or repeatedly. Both hypothalamic pCaMK-IIα and c-FOS expressions were increased by naloxone treatment in acutely administered morphine group, whereas only pCaMK-IIα expression was elevated by naloxone treatment in repeatedly administered morphine group. In contrast with the findings in morphine-treated group, only pCaMK-IIα expression was decreased by naloxone treatment in repeatedly administered β-endorphin group. Our results suggest that profiles of the withdrawal symptoms induced by morphine and β-endorphin administered supraspinally appear to be differentially regulated. The pCaMK-IIα and the c-FOS protein expression may play important roles for the regulation of naloxone-precipitated withdrawal symptoms such

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

    PubMed

    Galuppi, V

    1994-06-01

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

  7. Insulin Signaling And Insulin Resistance

    PubMed Central

    Beale, Elmus G.

    2013-01-01

    Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (e.g., 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. PMID:23111650

  8. Modest hyperglycemia prevents interstitial dispersion of insulin in skeletal muscle

    PubMed Central

    Kolka, Cathryn M.; Castro, Ana Valeria B.; Kirkman, Erlinda L.; Bergman, Richard N.

    2014-01-01

    Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake, but this is blocked in insulin resistance. As glucotoxicity is associated with endothelial dysfunction, the observed hyperglycemia in diet-induced obese dogs may inhibit insulin access to muscle cells, and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in modest hyperglycemia, similar to that induced by a high fat diet. METHODS During normoglycemic (100mg/dl) and moderately hyperglycemic (120mg/dl) clamps in anesthetized canines, sequential doses of insulin were injected into the vastus medialis of one hindlimb; the contra-lateral limb served as a control. Plasma samples were collected and analyzed for insulin content. Lymph vessels of the hind leg were also catheterized, and lymph samples were analyzed as an indicator of interstitial insulin concentration. RESULTS Insulin injection increased lymph insulin in normoglycemic animals, but not in hyperglycemic animals. Muscle glucose uptake was elevated in response to hyperglycemia, however the insulin-mediated glucose uptake in normoglycemic controls was not observed in hyperglycemia. Modest hyperglycemia prevented intra-muscularly injected insulin from diffusing through the interstitial space reduced insulin-mediated glucose uptake. CONCLUSION Hyperglycemia prevents the appearance of injected insulin in the interstitial space, thus reducing insulin action on skeletal muscle cells. PMID:25468139

  9. 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. PMID:23643758

  10. Therapeutic potential of intracerebroventricular replacement of modified human β-hexosaminidase B for GM2 gangliosidosis.

    PubMed

    Matsuoka, Kazuhiko; Tamura, Tomomi; Tsuji, Daisuke; Dohzono, Yukie; Kitakaze, Keisuke; Ohno, Kazuki; Saito, Seiji; Sakuraba, Hitoshi; Itoh, Kohji

    2011-06-01

    To develop a novel enzyme replacement therapy for neurodegenerative Tay-Sachs disease (TSD) and Sandhoff disease (SD), which are caused by deficiency of β-hexosaminidase (Hex) A, we designed a genetically engineered HEXB encoding the chimeric human β-subunit containing partial amino acid sequence of the α-subunit by structure-based homology modeling. We succeeded in producing the modified HexB by a Chinese hamster ovary (CHO) cell line stably expressing the chimeric HEXB, which can degrade artificial anionic substrates and GM2 ganglioside in vitro, and also retain the wild-type (WT) HexB-like thermostability in the presence of plasma. The modified HexB was efficiently incorporated via cation-independent mannose 6-phosphate receptor into fibroblasts derived from Tay-Sachs patients, and reduced the GM2 ganglioside accumulated in the cultured cells. Furthermore, intracerebroventricular administration of the modified HexB to Sandhoff mode mice restored the Hex activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma. These results suggest that the intracerebroventricular enzyme replacement therapy involving the modified HexB should be more effective for Tay-Sachs and Sandhoff than that utilizing the HexA, especially as a low-antigenic enzyme replacement therapy for Tay-Sachs patients who have endogenous WT HexB. PMID:21487393

  11. 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

  12. Two Cases of Allergy to Insulin in Gestational Diabetes

    PubMed Central

    Kim, Gi Jun; Kim, Shin Bum; Jo, Seong Il; Shin, Jin Kyeong; Kwon, Hee Sun; Jeong, Heekyung; Son, Jang Won; Lee, Seong Su; Kim, Sung Rae; Kim, Byung Kee

    2015-01-01

    Allergic reaction to insulin is uncommon since the introduction of human recombinant insulin preparations and is more rare in pregnant than non-pregnant females due to altered immune reaction during pregnancy. Herein, we report two cases of allergic reaction to insulin in gestational diabetes that were successfully managed. One case was a 33-year-old female using isophane-neutral protamine Hagedorn human insulin and insulin lispro. She experienced dyspnea, cough, urticaria and itching sensation at the sites of insulin injection immediately after insulin administration. We discontinued insulin therapy and started oral hypoglycemic agents with metformin and glibenclamide. The other case was a 32-year-old female using insulin lispro and insulin detemer. She experienced pruritus and burning sensation and multiple nodules at the sites of insulin injection. We changed the insulin from insulin lispro to insulin aspart. Assessments including immunoglobulin E (IgE), IgG, eosinophil, insulin antibody level and skin biopsy were performed. In the two cases, the symptoms were resolved after changing the insulin to oral agents or other insulin preparations. We report two cases of allergic reaction to human insulin in gestational diabetes due to its rarity. PMID:26435137

  13. Two Cases of Allergy to Insulin in Gestational Diabetes.

    PubMed

    Kim, Gi Jun; Kim, Shin Bum; Jo, Seong Il; Shin, Jin Kyeong; Kwon, Hee Sun; Jeong, Heekyung; Son, Jang Won; Lee, Seong Su; Kim, Sung Rae; Kim, Byung Kee; Yoo, Soon Jib

    2015-09-01

    Allergic reaction to insulin is uncommon since the introduction of human recombinant insulin preparations and is more rare in pregnant than non-pregnant females due to altered immune reaction during pregnancy. Herein, we report two cases of allergic reaction to insulin in gestational diabetes that were successfully managed. One case was a 33-year-old female using isophane-neutral protamine Hagedorn human insulin and insulin lispro. She experienced dyspnea, cough, urticaria and itching sensation at the sites of insulin injection immediately after insulin administration. We discontinued insulin therapy and started oral hypoglycemic agents with metformin and glibenclamide. The other case was a 32-year-old female using insulin lispro and insulin detemer. She experienced pruritus and burning sensation and multiple nodules at the sites of insulin injection. We changed the insulin from insulin lispro to insulin aspart. Assessments including immunoglobulin E (IgE), IgG, eosinophil, insulin antibody level and skin biopsy were performed. In the two cases, the symptoms were resolved after changing the insulin to oral agents or other insulin preparations. We report two cases of allergic reaction to human insulin in gestational diabetes due to its rarity. PMID:26435137

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

    PubMed Central

    Nasrallah, Sami N.; Reynolds, L. Raymond

    2012-01-01

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

  15. [Novel insulins].

    PubMed

    Eriksson, Johan G; Laine, Merja K

    2016-01-01

    Novel insulins have entered the market during recent years. The ultra-long acting insulins, insulin degludek and insulin glargine, the latter having a strength of 300 U/ml, exhibit a steady and predictable action curve. Studies have indicated that significantly fewer hypoglycemiae occur when using degludek in patients with either type 1 or type 2 diabetes, whereas similar evidence about glargine (300 U/mI) has been obtained in the treatment of type 2 diabetes. The long duration of action of both insulins brings long-needed flexibility to.their dosing. PMID:27089618

  16. Low-dose insulin infusions in diabetic patients with high insulin requirements.

    PubMed

    Dandona, P; Foster, M; Healey, F; Greenbury, E; Beckett, A G

    1978-08-01

    Six patients with high insulin requirements (range 120-3000 units daily) have been infused with much smaller doses (range 50-63 units daily) of insulin intravenously. All six maintained adequate glucose homoestasis on this regimen. It is suggested that subcutaneous tissue at the site of injection may alter insulin or impair its absorption. Insulin resistance in some patients may be due to these mechanisms.

  17. Biosimilar Insulins

    PubMed Central

    Hompesch, Marcus

    2014-01-01

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

  18. 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

  19. Insulin Increases Ceramide Synthesis in Skeletal Muscle

    PubMed Central

    Hansen, M. E.; Tippetts, T. S.; Anderson, M. C.; Holub, Z. E.; Moulton, E. R.; Swensen, A. C.; Prince, J. T.; Bikman, B. T.

    2014-01-01

    Aims. The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. Methods. Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. Results. In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. Conclusions. This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects. PMID:24949486

  20. Insulin-dependent (type I) diabetes mellitus.

    PubMed Central

    Rodger, W

    1991-01-01

    Insulin-dependent (type I) diabetes mellitus is a chronic disease characterized by hyperglycemia, impaired metabolism and storage of important nutrients, evidence of autoimmunity, and long-term vascular and neurologic complications. Insulin secretory function is limited. Cell membrane binding is not primarily involved. The goal of treatment is to relieve symptoms and to achieve blood glucose levels as close to normal as possible without severe hypoglycemia. However, even with education and self-monitoring of the blood glucose level, attaining recommended target values (plasma glucose level less than 8.0 mmol/L before main meals for adults) remains difficult. Human insulin offers no advantage in glycemic control but is important in the management and prevention of immune-related clinical problems (e.g., injection-site lipoatrophy, insulin resistance and allergy) associated with the use of beef or pork insulin. Therapy with one or two injections per day of mixed short-acting or intermediate-acting insulin preparations is a compromise between convenience and the potential for achieving target plasma glucose levels. Intensive insulin therapy with multiple daily injections or continuous infusion with an insulin pump improves mean glycated hemoglobin levels; however, it increases rates of severe hypoglycemia and has not been shown to decrease the incidence of clinically significant renal, retinal or neurologic dysfunction. Future prospects include automated techniques of insulin delivery, immunosuppression to preserve endogenous insulin secretion and islet transplantation. PMID:1933705

  1. Insulin oedema.

    PubMed Central

    Evans, D. J.; Pritchard-Jones, K.; Trotman-Dickenson, B.

    1986-01-01

    A 35 year old markedly underweight woman presented with uncontrolled diabetes. Following insulin therapy she developed gross fluid retention with extensive peripheral oedema, bilateral pleural effusions and weight gain of 18.8 kg in 22 days, accompanied by a fall in plasma albumin. She responded well to treatment with diuretics and salt-poor albumin, losing 10.3 kg in 6 days without recurrence of oedema. Severe insulin oedema is an uncommon complication of insulin therapy and may be due to effects of insulin on both vascular permeability and the renal tubule. Images Figure 2 PMID:3529068

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

    PubMed

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

    2016-05-01

    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.

  3. GLP-1 receptor agonism ameliorates hepatic VLDL overproduction and de novo lipogenesis in insulin resistance

    PubMed Central

    Taher, Jennifer; Baker, Christopher L.; Cuizon, Carmelle; Masoudpour, Hassan; Zhang, Rianna; Farr, Sarah; Naples, Mark; Bourdon, Celine; Pausova, Zdenka; Adeli, Khosrow

    2014-01-01

    Background/objectives Fasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein (VLDL). Recently, the incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production. Methods The fructose-fed Syrian golden hamster was employed as a model of diet-induced insulin resistance and VLDL overproduction. Hamsters were treated with the GLP-1R agonist exendin-4 by intraperitoneal (ip) injection for peripheral studies or by intracerebroventricular (ICV) administration into the 3rd ventricle for central studies. Peripheral studies were repeated in vagotomised hamsters. Results Short term (7–10 day) peripheral exendin-4 enhanced satiety and also prevented fructose-induced fasting dyslipidemia and hyperinsulinemia. These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma. The observed changes in fasting dyslipidemia could be partially explained by reduced respiratory exchange ratio (RER) thereby indicating a switch in energy utilization from carbohydrate to lipid. Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation. Despite these observations, GLP-1R activity could not be detected in primary hamster hepatocytes, thus leading to the investigation of a potential brain–liver axis functioning to regulate lipid metabolism. Short term (4 day) central administration of exendin-4 decreased body weight and food consumption and further prevented fructose-induced hypertriglyceridemia. Additionally, the peripheral lipid

  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. Regulation of rat MOR-1 gene expression after chronic intracerebroventricular administration of morphine

    PubMed Central

    ZHU, ZHI-PING; BADISA, RAMESH B.; PALM, DONALD E.; GOODMAN, CARL B.

    2012-01-01

    The μ-opioid receptor is the primary site for the action of morphine. In the present study, we investigated the regulation of the μ-opioid receptor mRNA levels in the locus ceruleus, ventral tegmental area, nucleus accumbens, and hypothalamus of the rat brain following intracerebroventricular administration of morphine for 7 days. The isolated mRNA from these regions was subjected to real-time quantitative RT-PCR to determine the regulation of μ-opioid receptor gene expression. It was observed that 7 days of treatment with morphine significantly down-regulated the μ-opioid receptor mRNA levels in the hypothalamus of the brain in comparison to the control group. However, the μ-opioid receptor levels in the locus ceruleus, ventral tegmental area, and nucleus accumbens regions remained the same as the control levels. Down-regulation of μ-opioid receptor mRNA levels in the hypothalamus region of the brain indicates the probable role of opioids to influence neuroendocrine function. The results further indicate that cellular adaptation for morphine tolerance is tissue-specific. These findings help us to understand the mechanism of morphine tolerance in various regions of the brain. PMID:22089925

  6. 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.

  7. 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. PMID:25421983

  8. Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice[S

    PubMed Central

    Coomans, Claudia P.; Geerling, Janine J.; Guigas, Bruno; van den Hoek, Anita M.; Parlevliet, Edwin T.; Ouwens, D. Margriet; Pijl, Hanno; Voshol, Peter J.; Rensen, Patrick C. N.; Havekes, Louis M.; Romijn, Johannes A.

    2011-01-01

    Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic clamp conditions stimulated the retention of both plasma triglyceride-derived FA and plasma albumin-bound FA in the various white adipose tissues (WAT) but not in other tissues, including brown adipose tissue (BAT). Intracerebroventricular (ICV) administration of insulin induced a similar pattern of tissue-specific FA partitioning. This effect of ICV insulin administration was not associated with activation of the insulin signaling pathway in adipose tissue. ICV administration of tolbutamide, a KATP channel blocker, considerably reduced (during hyperinsulinemic-euglycemic clamp conditions) and even completely blocked (during ICV administration of insulin) WAT-specific retention of FA from plasma. This central effect of insulin was absent in CD36-deficient mice, indicating that CD36 is the predominant FA transporter in insulin-stimulated FA retention by WAT. In diet-induced insulin-resistant mice, these stimulating effects of insulin (circulating or ICV administered) on FA retention in WAT were lost. In conclusion, in insulin-sensitive mice, circulating insulin stimulates tissue-specific partitioning of plasma-derived FA in WAT in part through activation of KATP channels in the CNS. Apparently, circulating insulin stimulates fatty acid uptake in WAT but not in BAT, directly and indirectly through the CNS. PMID:21700834

  9. Insulin delivery rate into plasma in normal and diabetic subjects

    PubMed Central

    Stern, Michael P.; Farquhar, John W.; Silvers, Abraham; Reaven, Gerald M.

    1968-01-01

    Removal of insulin-131I from plasma was studied in normal and diabetic subjects with both single injection and continuous infusion of isotope techniques. Patients were studied either in the fasting state or during steady-state hyperglycemia produced by a continuous intravenous glucose infusion. Steady-state plasma insulin concentration during these studies ranged from 10 to 264 μU/ml. Labeled insulin specific activity time curves consisted of more than one exponential, indicating that a multicompartmental system for insulin metabolism exists. A mathematical technique which is applicable to non-first order processes was used to calculate the rate at which insulin was lost irreversibly from the plasma insulin pool. A direct, linear relationship was found between insulin irreversible loss rate and plasma insulin concentration over the range of concentrations studied. This linearity implies lack of saturability of the insulin removal mechanism. Since the plasma insulin pool was in a steady state during these studies, insulin irreversible loss rate was equal to the rate at which newly secreted insulin was being delivered to the general circulation. Therefore, these results indicate that changes in plasma insulin concentration result from parallel changes in the rate of insulin delivery and not from changes in the opposite direction of the rate of insulin removal. A wide range of insulin delivery rates was found among patients with similar plasma glucose concentrations, suggesting that there exists considerable variability in responsiveness to endogenous insulin among these patients. PMID:5675421

  10. Insulin therapies: Current and future trends at dawn

    PubMed Central

    Yaturu, Subhashini

    2013-01-01

    Insulin is a key player in the control of hyperglycemia for type 1 diabetes patients and selective individuals in patients of type 2 diabetes. Insulin delivery systems that are currently available for the administration of insulin include insulin syringes, insulin infusion pumps, jet injectors and pens. The traditional and most predictable method for the administration of insulin is by subcutaneous injections. The major drawback of current forms of insulin therapy is their invasive nature. To decrease the suffering, the use of supersonic injectors, infusion pumps, sharp needles and pens has been adopted. Such invasive and intensive techniques have spurred the search for alternative, more acceptable methods for administering insulin. Several non-invasive approaches for insulin delivery are being pursued. The newer methods explored include the artificial pancreas with closed-loop system, transdermal insulin, and buccal, oral and pulmonary routes. This review focuses on the new concepts that are being explored for use in future. PMID:23493823

  11. Altered insulin distribution and metabolism in type I diabetics assessed by (123I)insulin scanning

    SciTech Connect

    Hachiya, H.L.; Treves, S.T.; Kahn, C.R.; Sodoyez, J.C.; Sodoyez-Goffaux, F.

    1987-04-01

    Scintigraphic scanning with (/sup 123/I)insulin provides a direct and quantitative assessment of insulin uptake and disappearance at specific organ sites. Using this technique, the biodistribution and metabolism of insulin were studied in type 1 diabetic patients and normal subjects. The major organ of (/sup 123/I)insulin uptake in both diabetic and normal subjects was the liver. After iv injection in normal subjects, the uptake of (/sup 123/I)insulin by the liver was rapid, with peak activity at 7 min. Activity declined rapidly thereafter, consistent with rapid insulin degradation and clearance. Rapid uptake of (/sup 123/I)insulin also occurred in the kidneys, although the uptake of insulin by the kidneys was about 80% of that by liver. In type 1 diabetic patients, uptake of (/sup 123/I)insulin in these organ sites was lower than that in normal subjects; peak insulin uptakes in liver and kidneys were 21% and 40% lower than those in normal subjects, respectively. The kinetics of insulin clearance from the liver was comparable in diabetic and normal subjects, whereas clearance from the kidneys was decreased in diabetics. The plasma clearance of (/sup 123/I)insulin was decreased in diabetic patients, as was insulin degradation, assessed by trichloroacetic acid precipitability. Thirty minutes after injection, 70.9 +/- 3.8% (+/- SEM) of (/sup 123/I)insulin in the plasma of diabetics was trichloroacetic acid precipitable vs. only 53.9 +/- 4.0% in normal subjects. A positive correlation was present between the organ uptake of (123I)insulin in the liver or kidneys and insulin degradation (r = 0.74; P less than 0.001).

  12. Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates tyrosine hydroxylase through extracellular signal-regulated kinase in rat striatum.

    PubMed

    Yu, Hyun Sook; Kim, Se Hyun; Park, Hong Geun; Kim, Yong Sik; Ahn, Yong Min

    2011-11-01

    Alteration in dopamine neurotransmission has been reported to be involved in the mania of bipolar disorder. Tyrosine hydroxylase (TH) is the rate-limiting enzyme that is crucial for dopamine biosynthesis, and its activity is tightly regulated by phosphorylation at multiple N-terminal serine residues. Previously, we have reported that intracerebroventricular (ICV) injection of ouabain, a selective Na/K-ATPase inhibitor, induces hyperactivity in rats that mimics manic symptoms related to the activation of extracellular signal-regulated protein kinase1/2 (ERK1/2), which plays crucial roles in the modulation of TH phosphorylation. In this study, we investigated the effects of ICV injection of ouabain on TH phosphorylation in rat striatum and the involvement of ERK1/2 in ouabain-induced TH activation. ICV ouabain induced an acute dose-dependent increase in locomotor activity and in TH phosphorylation in rat striatum. TH phosphorylation at Ser19 was significantly increased with 100, 500, and 1000μM ouabain, and phosphorylation at Ser31 and Ser40 was significantly increased with 500 and 1000μM. We also found that ICV pretreatment with U0126, a specific MEK1/2 inhibitor, attenuated the 1000μM ouabain-induced increase in TH phosphorylation at Ser19, Ser31, and Ser40, as well as the hyperactivity of rats. Moreover, the increased phosphorylation of TH (Ser19, Ser31, and Ser40) was maintained until 8h after single administration ouabain was accompanied by increased phosphorylation of ERK1/2 (Thr202/Tyr204) and p90RSK (Thr359/Ser363). These findings imply that TH activation of the ERK1/2 signal pathway could play an important role in ouabain-induced hyperactivity of rats, a mania model. PMID:21871514

  13. Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease.

    PubMed

    Barilar, J Osmanovic; Knezovic, A; Grünblatt, E; Riederer, P; Salkovic-Petrisic, M

    2015-04-01

    Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin-resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods ≤3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods ≤9 months after STZ-icv treatment. Male Wistar rats were given vehicle (control)- or STZ (3 mg/kg)-icv injection and killed 0.5, 1, 3, 6 and 9 months afterwards. Insulin-1 (Ins-1), IR, phospho- and total (p/t)-glycogen synthase kinase 3-β (GSK-3β), p/t-tau and insulin degrading enzyme (IDE) mRNA and/or protein were measured. Acute upregulation of tau and IR mRNA (p < 0.05) was followed by a pronounced downregulation of Ins-1, IR and IDE mRNA (p < 0.05) in the course of time. Acute decrement in p/t-tau and p/t-GSK-3β ratios (p < 0.05) was followed by increment in both ratios (3-6 months, p < 0.05) after which p/t-tau ratio demonstrated a steep rise and p/t-GSK-3β ratio a steep fall up to 9 months (p < 0.05). Acute decline in IDE and IR expression (p < 0.05) was followed by a slow progression of the former and a slow recovery of the latter in 3-9 months. Results indicate a biphasic pattern in time dependency of onset and progression of changes in brain insulin signalling of STZ-icv model (partly reversible acute toxicity and chronic AD-like changes) which should be considered when using this model as a tool in translational sAD research. PMID:25503661

  14. Insulin Test

    MedlinePlus

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

  15. 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

    2011-12-01

    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

  16. Intracerebroventricular application of S100B selectively impairs pial arteriolar dilating function in rats.

    PubMed

    Changyaleket, Benjarat; Xu, Haoliang; Vetri, Francesco; Valyi-Nagy, Tibor; Paisansathan, Chanannait; Chong, Zhao Zhong; Pelligrino, Dale A; Testai, Fernando D

    2016-03-01

    S100B is an astrocyte-derived protein that can act through the receptor for advanced glycation endproducts (RAGE) to mediate either "trophic" or "toxic" responses. Its levels increase in many neurological conditions with associated microvascular dysregulation, such as subarachnoid hemorrhage (SAH) and traumatic brain injury. The role of S100B in the pathogenesis of microvasculopathy has not been addressed. This study was designed to examine whether S100B alters pial arteriolar vasodilating function. Rats were randomized to receive (1) artificial cerebrospinal fluid (aCSF), (2) exogenous S100B, and (3) exogenous S100B+the decoy soluble RAGE (sRAGE). S100B was infused intracerebroventricularly (icv) using an osmotic pump and its levels in the CSF were adjusted to achieve a concentration similar to what we observed in SAH. After 48 h of continuous icv infusion, a cranial window/intravital microscopy was applied to animals for evaluation of pial arteriolar dilating responses to sciatic nerve stimulation (SNS), hypercapnia, and topical suffusion of vasodilators including acetylcholine (ACh), s-nitroso-N-acetyl penicillamine (SNAP), or adenosine (ADO). Pial arteriolar dilating responses were calculated as the percentage change of arteriolar diameter in relation to baseline. The continuous S100B infusion for 48 h was associated with reduced responses to the neuronal-dependent vasodilator SNS (p<0.05) and the endothelial-dependent vasodilator ACh (p<0.05), compared to controls. The inhibitory effects of S100B were prevented by sRAGE. On the other hand, S100B did not alter the responses elicited by vascular smooth muscle cell-dependent vasodilators, namely hypercapnia, SNAP, or ADO. These findings indicate that S100B regulates neuronal and endothelial dependent cerebral arteriolar dilation and suggest that this phenomenon is mediated through RAGE-associated pathways. PMID:26773687

  17. Differential effect of low doses of intracerebroventricular corticotropin-releasing factor in forced swimming test.

    PubMed

    García-Lecumberri, C; Ambrosio, E

    2000-11-01

    In this work, we studied the effect of low doses of intracerebroventricular corticotropin-releasing factor (CRF) in six sessions of forced swimming test (FST). When CRF (0.01 and 0.1 microg) was administered pre-test, results showed that the 0.1-microg dose significantly increased swimming in SESSION2, SESSION3 and SESSION4, while the 0.01-microg dose proved ineffective. When CRF (0.1 and 0.03 microg) was administered post-test to evaluate retention of swimming response, the dose of 0.1 microg impaired retention, while the dose of 0.03 microg improved it, although these effects only reached significance in SESSION2. In an additional session (SESSION6), testing long-term retention of this swimming response, the 0.1-microg dose significantly impaired retention, whereas the 0.03-microg dose proved ineffective. A high dose of CRF (1 microg) was also included as a control of previous results [García-Lecumberri C, Ambrosio E. Role of corticotropin-releasing factor in forced swimming test. Eur J Pharmacol 1998;343:17-26]. In all the FST sessions, this high dose increased swimming when administered pre-test, while impairing retention when administered post-test. Preliminary data obtained with low doses of CRF suggest that a differential effect on retention of swimming response seems to exist depending on the dose, whereas a high dose of CRF clearly impairs retention. The role of CRF in learning and memory processes in FST is discussed.

  18. Can a new ultra-long-acting insulin analogue improve patient care? Investigating the potential role of insulin degludec.

    PubMed

    Robinson, Jennifer D; Neumiller, Joshua J; Campbell, R Keith

    2012-12-24

    The basal-bolus concept of delivering insulin to diabetic patients makes physiological sense, as it mimics normal insulin release in people without diabetes. In line with this concept, a major effort put forth by insulin manufacturers has been to develop the ideal exogenous basal insulin product. The perfect basal insulin product would be injected into subcutaneous tissue without causing irritation, release insulin continuously at a constant rate for at least 24 hours, be stable, not contribute to weight gain, have a low risk of allergic reactions and, very importantly, minimize the risk of hypoglycaemia. While the perfect insulin has not yet been discovered, advancements are still being made. Insulin degludec is an ultra-long-acting basal insulin analogue that possesses a flat, stable glucose-lowering effect in patients with type 1 or type 2 diabetes mellitus. Insulin degludec achieves these pharmacokinetic properties by forming soluble multihexamers upon subcutaneous injection, resulting in the formation of a depot in the subcutaneous tissue that is slowly released and absorbed into circulation. Insulin degludec has been associated with slightly less weight gain and fewer nocturnal hypoglycaemic episodes when compared with insulin glargine in some, but not all, clinical studies. This article briefly reviews current evidence for the use of insulin degludec in patients with type 1 or type 2 diabetes mellitus and discusses the potential impact of this new basal insulin on clinical practice. PMID:23145524

  19. Diabetes therapy trials with inhaled insulin.

    PubMed

    Fineberg, Samuel Edwin

    2006-07-01

    Administration of insulin by inhalation was first attempted > 50 years ago. At that time, little was known concerning effective delivery systems and insulin formulations. The recent development of pulmonary delivery systems for the administration of insulin is driven by the reluctance of patients and their providers to initiate insulin earlier in the course of Type 2 diabetes, the desire to reduce the number of daily insulin injections for both Type 1 and 2 patients, and the recent emphasis on intensified glycaemic control including postprandial glycaemic control. The deep lung is a unique mucosal tissue having a surface area of > 100 m2 and is readily accessible both to the external environment and to drug delivery, provided that appropriate conditions are met. There have been four mid- to late-phase pulmonary insulin programmes using modern inhalation devices that will be reported in this paper. The programmes differ in the choice of delivery systems, the formulations of insulin and reported bioavailability, pharmacokinetic and glucodynamic profiles and adverse events. However, all systems successfully deliver insulin to the deep lung and biological effectiveness compares favourably with injected subcutaneous insulins.

  20. Peripheral and centrally mediated effects of insulin on small intestinal transit in healthy mice.

    PubMed

    Peddyreddy, M K; Rao, K R

    2006-07-01

    1. Insulin is the drug of choice in the management of type 1 diabetes mellitus. Approximately 76% of diabetic patients suffer from gastrointestinal disorders. An important area of investigating the inherent effect of insulin on small intestinal transit (SIT) remains unexplored. Hence, the present study was planned to investigate the effects of insulin (2 x 10(-6), 2 x 10(-3) and 2 U/kg) on small intestinal transit following two different routes of administration in healthy animals. 2. Insulin or vehicle was administered subcutaneously or intracerebroventricularly in eight groups of healthy, overnight-fasted mice. Blood glucose (BG) levels were measured 2 min before insulin administration and at the time coinciding with SIT determination. Small intestinal transit was determined 50 min after insulin administration using the charcoal meal method. 3. Following subcutaneous administration, the lowest dose of insulin (2 x 10(-6) U/kg) produced a significant acceleration in SIT without altering BG levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with a significant fall in BG levels. 4. Following intracerebroventricular administration, the lowest dose of insulin (2 x 10(-6) U/kg) attenuated SIT, without producing any alteration in BG levels, but the highest dose (2 U/kg) mimicked the effects seen following subcutaneous administration. Peripherally administered insulin produced significant acceleration of SIT at lower doses (2 x 10(-6) or 2 x 10(-3) mU/kg) compared with centrally administered insulin at similar doses. However, at the highest dose of insulin (2 U/kg), both routes (s.c. and i.c.v.) produced acceleration of SIT. 5. In the present study, peripherally and centrally administered insulin at 2 x 10(-6) U/kg produced contrasting effects on SIT, without any hypoglycaemia. However, 2 U/kg insulin accelerated SIT similarly following both s.c. and i.c.v. administration that was associated with hypoglycaemia in

  1. Resolution of lipohypertrophy following change of short-acting insulin to insulin lispro (Humalog).

    PubMed

    Roper, N A; Bilous, R W

    1998-12-01

    Lipohypertrophy as a local complication of insulin therapy is well recognized. Despite improvements in insulin purity and the introduction of recombinant human insulin its prevalence has remained high. Rotation of injection sites can reduce the frequency of the problem but does not abolish it. The importance of this complication is not only cosmetic but also in its impact on insulin absorption, and hence glycaemic control. We report a patient who had intractable lipohypertrophy with human recombinant insulin but experienced no such problem when converted onto the insulin analogue lispro. We suggest that the faster speed of absorption of insulin lispro may lead to less hypertrophic stimulation of subcutaneous adipocytes. This difference may be clinically useful in susceptible individuals.

  2. Diabetes and Insulin

    MedlinePlus

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

  3. 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

  4. 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

  5. Overview of Clinical Trial Program and Applicability of Insulin Degludec/Insulin Aspart in Diabetes Management.

    PubMed

    Bantwal, Ganapathi; Wangnoo, Subhash K; Shunmugavelu, M; Nallaperumal, S; Harsha, K P; Bhattacharyya, Arpandev

    2015-05-01

    Insulin degludec/insulin aspart (IDegAsp) is the first soluble coformulation combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In patients with uncontrolled type 2 diabetes (T2DM) previously treated with insulins, IDegAsp twice daily effectively improves glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels with fewer hypoglycaemic episodes versus premix insulins. Further, insulin initiation with IDegAsp once daily provides superior long-term glycaemic control compared to insulin glargine with similar FPG and insulin doses, and numerically lower rates of overall and nocturnal hypoglycaemia. In patients with type 1 diabetes mellitus (T1DM), IDegAsp once daily and IAsp at remaining meals provides more convenient three injection regimen per day over conventional 4-5 injections based basal-bolus therapy. IDegAsp is an appropriate and reasonable option for intensifying insulin therapy in patients with T2DM and a relatively less complex treatment option for the management of T1DM. PMID:26548031

  6. 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.

  7. Comparison of daily glucose excursion by continuous glucose monitoring between type 2 diabetic patients receiving preprandial insulin aspart or postprandial insulin glulisine.

    PubMed

    Ohta, Akio; Arai, Kaori; Nishine, Ami; Sada, Yoshiyuki; Kato, Hiroyuki; Fukuda, Hisashi; Asai, Shiko; Nagai, Yoshio; Katabami, Takuyuki; Tanaka, Yasushi

    2013-01-01

    Insulin glulisine (Glu) is a rapidly-acting insulin analog with a faster onset of action than the other insulin analogs of its class, which are insulin aspart (Asp) and insulin lispro (Lisp). While insulin Glu is usually injected just before meals, postprandial injection may help to avoid unexpected postprandial hypoglycemia or hyperglycemia by adjusting the insulin dosage according to food intake. However, the effect of postprandial insulin Glu on the glucose profile has not been evaluated. The aim of this study was to compare daily glucose excursion by continuous glucose monitoring (CGM) between multiple daily doses of preprandial insulin Asp or postprandial insulin Glu. In a randomized cross-over trial, we performed CGM to evaluate the 48-hour glucose profile during treatment with the same dosage of insulin Asp just before each meal in 12 hospitalized patients with type 2 diabetes. Patients also received the same dosage of long-acting insulin glargine at bedtime. The average glucose level, standard deviation of the glucose level, mean amplitude of glucose excursion, and daily glucose profile did not differ between preprandial Asp and postprandial Glu. The incidence of hypoglycemic episodes (glucose level<70 mg/dL with or without symptoms) and the area under the curve of glucose<70 mg/dL also did not differ between the two insulin regimens. Multiple daily injections of preprandial Asp and postprandial Glu achieved the same daily glucose excursion profile. Postprandial injection of Glu may provide greater flexibility for patients who require insulin therapy. PMID:23047542

  8. Worldwide Injection Technique Questionnaire Study: Population Parameters and Injection Practices.

    PubMed

    Frid, Anders H; Hirsch, Laurence J; Menchior, Astrid R; Morel, Didier R; Strauss, Kenneth W

    2016-09-01

    From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries took part in one of the largest surveys ever performed in diabetes. The goal was to assess patient characteristics, as well as historical and practical aspects of their injection technique. Results show that 4- and 8-mm needle lengths are each used by nearly 30% of patients and 5- and 6-mm needles each by approximately 20%. Higher consumption of insulin (as measured by total daily dose) is associated with having lipohypertrophy (LH), injecting into LH, leakage from the injection site, and failing to reconstitute cloudy insulin. Glycated hemoglobin values are, on average, 0.5% higher in patients with LH and are significantly higher with incorrect rotation of sites and with needle reuse. Glycated hemoglobin values are lower in patients who distribute their injections over larger injection areas and whose sites are inspected routinely. The frequencies of unexpected hypoglycemia and glucose variability are significantly higher in those with LH, those injecting into LH, those who incorrectly rotate sites, and those who reuse needles. Needles associated with diabetes treatment are the most commonly used medical sharps in the world. However, correct disposal of sharps after use is critically suboptimal. Many used sharps end up in public trash and constitute a major accidental needlestick risk. Use of these data should stimulate renewed interest in and commitment to optimizing injection practices in patients with diabetes.

  9. Worldwide Injection Technique Questionnaire Study: Population Parameters and Injection Practices.

    PubMed

    Frid, Anders H; Hirsch, Laurence J; Menchior, Astrid R; Morel, Didier R; Strauss, Kenneth W

    2016-09-01

    From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries took part in one of the largest surveys ever performed in diabetes. The goal was to assess patient characteristics, as well as historical and practical aspects of their injection technique. Results show that 4- and 8-mm needle lengths are each used by nearly 30% of patients and 5- and 6-mm needles each by approximately 20%. Higher consumption of insulin (as measured by total daily dose) is associated with having lipohypertrophy (LH), injecting into LH, leakage from the injection site, and failing to reconstitute cloudy insulin. Glycated hemoglobin values are, on average, 0.5% higher in patients with LH and are significantly higher with incorrect rotation of sites and with needle reuse. Glycated hemoglobin values are lower in patients who distribute their injections over larger injection areas and whose sites are inspected routinely. The frequencies of unexpected hypoglycemia and glucose variability are significantly higher in those with LH, those injecting into LH, those who incorrectly rotate sites, and those who reuse needles. Needles associated with diabetes treatment are the most commonly used medical sharps in the world. However, correct disposal of sharps after use is critically suboptimal. Many used sharps end up in public trash and constitute a major accidental needlestick risk. Use of these data should stimulate renewed interest in and commitment to optimizing injection practices in patients with diabetes. PMID:27594185

  10. Exenatide Injection

    MedlinePlus

    ... normally and therefore cannot control the amount of sugar in the blood). Exenatide is in a class ... stimulating the pancreas to secrete insulin when blood sugar levels are high. Insulin helps move sugar from ...

  11. Aprotinin induced lipohypertrophy and glomerulonephritis in an insulin dependent diabetic.

    PubMed

    Dandona, P; Mier, A; Boag, F; Chappell, M; Beckett, A G

    1985-07-01

    In an insulin dependent diabetic who was hyperglycaemic and ketotic despite 3,000 u of insulin injected subcutaneously in 2 divided doses daily, 50 u of intravenous insulin infused over 24 hr restored normal glucose homeostasis. A combination of insulin (800 u) and aprotinin (10,000 u) given twice daily also produced adequate glucose homeostasis for a period of 12 months. The patient then developed local hypertrophy of subcutaneous tissue at the injection site and her diabetic control deteriorated. Non-selective proteinuria followed and she developed nephrotic syndrome. Renal biopsy revealed a membraneous glomerulonephritis with subepithelial immune complexes, appearances consistent with a drug-induced glomerulonephritis. Withdrawal of aprotinin led to a gradual remission of nephrotic syndrome and proteinuria over several months. During this period, her diabetes was well controlled with continuous subcutaneous infusion of insulin at a dose of 500 u/24 hr. This case report demonstrates: the effective use of aprotinin for prolonged periods in insulin dependent diabetics with abnormal absorption of subcutaneously injected insulin; aprotinin induced lipohypertrophy which was not observed when insulin was injected alone; aprotinin-associated glomerulonephritis and nephrotic syndrome; the effective use of CSII--at higher insulin doses--in such patients with subcutaneous malabsorption of insulin.

  12. Insulin degludec. Uncertainty over cardiovascular harms.

    PubMed

    2014-06-01

    Insulin isophane (NPH) is the standard long-acting human insulin for patients with type 1 and type 2 diabetes. Long-acting human insulin analogues are also available: insulin glargine and insulin detemir. Uncertainties remain concerning their long-term adverse effects. Insulin degludec (Tresiba, Novo Nordisk) is another long-acting human insulin analogue, also approved in the EU for patients with type 1 and type 2 diabetes. It was authorised at a concentration of 100 units per ml, like other insulins, and also at a concentration of 200 units per ml. There are no comparative data on insulin degludec 200 units per ml in patients using high doses of insulin. Insulin degludec has mainly been evaluated in ten randomised, unblinded, "non-inferiority" trials lasting 26 to 52 weeks, nine versus insulin glargine and one versus insulin detemir. Insulin degludec was administered at a fixed time each evening, or in either the morning or evening on alternate days, at varying intervals of 8 to 40 hours between doses. Efficacy in terms of HbA1c control was similar to that of the other insulin analogues administered once a day. The frequency of severe hypoglycaemia was similar in the groups treated with insulin degludec and those treated with the other insulins (10% to 12% among patients with type 1 diabetes and less than 5% in patients with type 2 diabetes). Deaths and other serious adverse events were similarly frequent in the different groups. A meta-analysis of clinical trials, carried out by the US Food and Drug Administration, suggested an increase of about 60% in the incidence of cardiovascular complications, based on a composite endpoint combining myocardial infarction, stroke and cardiovascular death. Other adverse effects observed in these trials were already known to occur with human insulin and its analogues, including weight gain, hypersensitivity reactions, reactions at the injection site, etc. The trials were too short in duration to assess long-term harms

  13. 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

    2015-01-01

    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. PMID:26498972

  14. 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 ...

  15. Suspension of basal insulin to avoid hypoglycemia in type 1 diabetes treated with insulin pump

    PubMed Central

    Sánchez-Hernández, Rosa M; Rodríguez-Cordero, Julia; Jiménez-Ortega, Angelines; Nóvoa, Francisco J

    2015-01-01

    Summary Treatment with continuous s.c. insulin infusion (CSII) provides better glycemic control and lower risk of hypoglycemia than conventional therapy with multiple daily insulin injections. These benefits have been related to a more reliable absorption and an improved pharmacokinetic profile of insulin delivered through CSII therapy. However, even for patients treated with CSII, exaggerated postmeal hyperglycemic excursions and late postabsorptive hypoglycemia can still constitute a therapeutic challenge. Two female patients with type 1 diabetes who began treatment with CSII required to increase their previous breakfast insulin-to-carbohydrate ratio in order to achieve postprandial glycemic goals. However, they simultaneously presented recurrent episodes of late hypoglycemia several hours after breakfast bolus. Advancing the timing of the bolus was ineffective and bothersome for patients. In both cases, the best therapeutic option was to set a basal insulin rate of zero units per hour during 6 h after breakfast. Even so, they need to routinely take a midmorning snack with 10–20 g of carbohydrates to avoid late postabsorptive hypoglycemia. They have been using this insulin schedule for about 3 years without complications. The action of prandial insulin delivered through insulin pumps can be inappropriately delayed for the requirements of some patients. Although suspension of basal rate can be an acceptable therapeutic alternative for them, these cases demonstrate that new strategies to improve the bioavailability of prandial insulin infused through CSII are still needed. Learning points CSII remains the most physiologically suitable system of insulin delivery available today.Additionally, the duration of action of prandial insulin delivered through insulin pumps can be excessively prolonged in some patients with type 1 diabetes.These patients can present recurrent late episodes of hypoglycemia several hours after the administration of insulin boluses

  16. 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

  17. 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

  18. Worldwide Injection Technique Questionnaire Study: Injecting Complications and the Role of the Professional.

    PubMed

    Frid, Anders H; Hirsch, Laurence J; Menchior, Astrid R; Morel, Didier R; Strauss, Kenneth W

    2016-09-01

    From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries participated in one of the largest surveys ever performed in diabetes. The first results of this survey are published elsewhere in this issue. Herein we report that the most common complication of injecting insulin is lipohypertrophy (LH), which was self-reported by 29.0% of patients and found by physical examination in 30.8% by health care professionals (HCPs). Patients with LH consumed a mean of 10.1 IU more insulin daily than patients without LH. Glycated hemoglobin levels averaged 0.55% higher in patients with vs without LH. Lipohypertrophy was associated with higher rates of unexplained hypoglycemia and glycemic variability as well as more frequent diabetic ketoacidosis, incorrect rotation of injection sites, use of smaller injection zones, longer duration of insulin use, and reuse of pen needles (each P<.05). Routine inspection of injection sites by the HCP was associated with lower glycated hemoglobin levels, less LH, and more correct injection site rotation. Patients were also more likely to rotate correctly if they received injection instructions from their HCP in the past 6 months. Fewer than 40% of patients claimed to have gotten such instructions in the past 6 months, and 10% said that they have never received training on how to inject correctly despite injecting for a mean of nearly 9 years. Use of these data should stimulate renewed commitment to optimizing insulin injection practices. PMID:27594186

  19. Worldwide Injection Technique Questionnaire Study: Injecting Complications and the Role of the Professional.

    PubMed

    Frid, Anders H; Hirsch, Laurence J; Menchior, Astrid R; Morel, Didier R; Strauss, Kenneth W

    2016-09-01

    From February 1, 2014, through June 30, 2015, 13,289 insulin-injecting patients from 423 centers in 42 countries participated in one of the largest surveys ever performed in diabetes. The first results of this survey are published elsewhere in this issue. Herein we report that the most common complication of injecting insulin is lipohypertrophy (LH), which was self-reported by 29.0% of patients and found by physical examination in 30.8% by health care professionals (HCPs). Patients with LH consumed a mean of 10.1 IU more insulin daily than patients without LH. Glycated hemoglobin levels averaged 0.55% higher in patients with vs without LH. Lipohypertrophy was associated with higher rates of unexplained hypoglycemia and glycemic variability as well as more frequent diabetic ketoacidosis, incorrect rotation of injection sites, use of smaller injection zones, longer duration of insulin use, and reuse of pen needles (each P<.05). Routine inspection of injection sites by the HCP was associated with lower glycated hemoglobin levels, less LH, and more correct injection site rotation. Patients were also more likely to rotate correctly if they received injection instructions from their HCP in the past 6 months. Fewer than 40% of patients claimed to have gotten such instructions in the past 6 months, and 10% said that they have never received training on how to inject correctly despite injecting for a mean of nearly 9 years. Use of these data should stimulate renewed commitment to optimizing insulin injection practices.

  20. 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)

  1. 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)

  2. Effects of intravenous neuropeptide Y on insulin secretion and insulin sensitivity in skeletal muscle in normal rats.

    PubMed

    Vettor, R; Pagano, C; Granzotto, M; Englaro, P; Angeli, P; Blum, W F; Federspil, G; Rohner-Jeanrenaud, F; Jeanrenaud, B

    1998-11-01

    Intracerebroventricular administration of neuropeptide Y to normal rats induces a syndrome characterised by obesity, hyperinsulinaemia, insulin resistance and over expression of the adipose tissue ob gene. Little is known about the effect of circulating neuropeptide Y on glucose metabolism, insulin secretion and leptin. We therefore aimed to evaluate the effect of an intravenous infusion of neuropeptide Y on glucose disposal, endogenous glucose production, whole body glycolytic flux, and glucose storage as assessed during euglycaemic hyperinsulinaemic clamp. In addition, the insulin-stimulated glucose utilisation index in individual tissues was measured by the 2-deoxy-[1-3H]-glucose technique. The effect of neuropeptide Y on insulin secretion was evaluated by hyperglycaemic clamp. Infusion did not induce any change in endogenous glucose production during basal conditions or at the end of the clamp. Glucose disposal was significantly increased in the rats given neuropeptide Y compared with controls (27.8 +/- 1.3 vs 24.3 +/- 1.6 mg x min(-1) x kg(-1); p < 0.05) as was the glycolytic flux (18.9 +/- 1.6 vs 14.4 +/- 0.8 mg x min(-1) x kg(-1); p < 0.05), while glucose storage was comparable in the two groups. In skeletal muscle, the glucose utilisation index was increased significantly in rats given neuropeptide Y. The glucose utilisation index in subcutaneous and epididimal adipose tissue was not significantly different between the two groups. Plasma leptin was significantly increased by hyperinsulinaemia, but was not affected by neuropeptide Y infusion. Both the early and late phase of the insulin response to hyperglycaemia were significantly reduced by neuropeptide Y. In conclusion neuropeptide Y infusion may increase insulin-induced glucose disposal in normal rats, accelerating its utilisation through the glycolytic pathway. Neuropeptide Y reduces both phases of the insulin response to hyperglycaemia.

  3. 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.

  4. Massive insulin overdose managed by monitoring daily insulin levels.

    PubMed

    Mork, Tyler A; Killeen, Colin T; Patel, Neel K; Dohnal, James M; Karydes, Harry C; Leikin, Jerrold B

    2011-09-01

    We present a case of a significant insulin overdose that was managed by monitoring daily plasma insulin levels. A 39-year-old male with poorly controlled diabetes mellitus presented to the Emergency Department via emergency medical services after an attempted suicide by insulin overdose. In the attempted suicide, he injected 800 U of insulin lispro and 3800 U of insulin glargine subcutaneously over several parts of his abdomen. The patient was conscious upon arrival to the emergency department. His vital parameters were within normal range. The abdominal examination, in particular, was nonfocal and showed no evidence of hematomas. He was awake, alert, conversant, tearful, and without any focal deficits. An infusion of 10% dextrose was begun at 100 mL/h with hourly blood glucose (BG) checks. The patient was transferred to the intensive care unit where his BG began to decrease and fluctuate between 50 and 80 mg/dL, and the rate of 10% dextrose was increased to 200 mL/h where it was maintained for the next 48 hours. The initial plasma insulin level was found to be 3712.6 uU/mL (reference range 2.6-31.1 uU/mL). At 10 hours, this had decreased to 1582.1 uU/ml. On five occasions, supplemental dextrose was needed when the BG was <70 mg/dL. Thirty-four hours after admission, the plasma insulin level was 724.8 uU/mL. Fifty-eight hours after admission, the plasma insulin level was 321.2 uU/mL, and the 10% dextrose infusion was changed to 5% dextrose solution at 200 mL/h. The plasma insulin levels continued to fall daily to 112.7 uU/mL at 80 hours and to 30.4 uU/mL at 108 hours. He was transferred to an inpatient psychiatric facility 109 hours after initial presentation. Monitoring daily plasma insulin levels and adjusting treatment on a day-to-day basis in terms of basal glucose infusions provides fewer opportunities for episodic hypoglycemia. Furthermore, it was easier to predict daily glucose requirements and eventual medical clearance based on the plasma levels.

  5. Oral insulin--a perspective.

    PubMed

    Raj, N K Kavitha; Sharma, Chandra P

    2003-01-01

    Diabetes mellitus is generally controlled quite well with the administration of oral medications or by the use of insulin injections. The current practice is the use of one or more doses, intermediate or long acting insulin per day. Oral insulin is a promising yet experimental method providing tight glycemic control for patients with diabetes. A biologically adhesive delivery systems offer important advantage over conventional drug delivery systems. The engineered polymer microspheres made of erodable polymer display strong adhesive interactions with gastrointestinal mucus and cellular lining can traverse both the mucosal epithelium and the follicle associated epithelium covering the lymphoid tissue of Peyer's patches. Alginate, a natural polymer recovered from seaweed is being developed as a nanoparticle for the delivery of insulin without being destroyed in the stomach. Alginate is in fact finding application in biotechnology industry as thickening agent, a gelling agent and a colloid stabilizer. Alginate has in addition, several other properties that have enabled it to be used as a matrix for entrapment and for the delivery of a variety of proteins such as insulin and cells. These properties include: a relatively inert aqueous environment within the matrix; a mild room temperature encapsulation process free of organic solvents; a high gel porosity which allows for high diffusion rates of macromolecules; the ability to control this porosity with simple coating procedures and dissolution and biodegradation of the system under normal physiological conditions.

  6. 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.

  7. Patient safety and minimizing risk with insulin administration - role of insulin degludec.

    PubMed

    Aye, Myint M; Atkin, Stephen L

    2014-01-01

    Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long

  8. Patient safety and minimizing risk with insulin administration – role of insulin degludec

    PubMed Central

    Aye, Myint M; Atkin, Stephen L

    2014-01-01

    Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long

  9. Pegfilgrastim Injection

    MedlinePlus

    ... a pre-filled automatic injection device (On-body Injector) to inject subcutaneously (under the skin). If you ... a pre-filled automatic injection device (On-body Injector), the device will usually be applied to your ...

  10. 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 ...

  11. 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 ...

  12. Romidepsin Injection

    MedlinePlus

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

  13. 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

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

    PubMed

    Grissinger, Matthew; Lease, Michael

    2003-02-01

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

  15. 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.

  16. Long-Term Effects of Intracerebroventricular Streptozotocin Treatment on Adult Neurogenesis in the Rat Hippocampus.

    PubMed

    Sun, Ping; Knezovic, Ana; Parlak, Milena; Cuber, Jacqueline; Karabeg, Margherita M; Deckert, Jürgen; Riederer, Peter; Hua, Qian; Salkovic-Petrisic, Melita; Schmitt, Angelika G

    2015-01-01

    Altered adult hippocampal neurogenesis (AN) plays a role in the etiopathology of Alzheimer's disease (AD), a disorder characterized by a progressive loss of memory and spatial orientation impairment. Diabetes is shown to be one risk factor for the development of the sporadic form of AD (sAD), which affects >95% of AD patients. Streptozotocin intracerebroventricularily (STZ icv) treated rats, which develop an insulin-resistant brain state and learning and memory deficits preceding amyloid beta and tau pathology, may act as an appropriate animal model for sAD. The goal of our quantitative immunohistochemistry study was to compare short-term (1 month) and long-term (3 months) effects of STZ icv treatment on different AN stages. Applying MCM2 antibodies we quantified cell (e.g. stem cell) proliferation, by the use of NeuroD and DCX antibodies we analyzed immature neurons. BrdU incorporation with approximately 27 days of survival before sacrifice allowed us to quantify and identify surviving newborn cells. Performing co-localization studies with antibodies detecting BrdU and cell-type specific markers we could confirm that STZ treatment does not affect the differentiation fate of newly generated cells. Whereas STZ icv treatment does not seem to considerably influence cell proliferation over a shortterm period (1 month), in the long-term (3 months) it significantly decreased generation of immature and mature neurons. This reduction seen after 3 months was specific for the septal hippocampus, discussed to be important for spatial learning. Moreover, AN changes display the same timeline as the development of amyloid beta pathology in this animal model of sAD.

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

    PubMed

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

    2015-05-01

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

  18. Overexpression of Insulin Degrading Enzyme could Greatly Contribute to Insulin Down-regulation Induced by Short-Term Swimming Exercise.

    PubMed

    Kim, Min Sun; Goo, Jun Seo; Kim, Ji Eun; Nam, So Hee; Choi, Sun Il; Lee, Hye Ryun; Hwang, In Sik; Shim, Sun Bo; Jee, Seung Wan; Lee, Su Hae; Bae, Chang Joon; Cho, Jung Sik; Cho, Jun Yong; Hwang, Dae Youn

    2011-03-01

    Exercise training is highly correlated with the reduced glucose-stimulated insulin secretion (GSIS), although it enhanced insulin sensitivity, glucose uptake and glucose transporter expression to reduce severity of diabetic symptoms. This study investigated the impact of short-term swimming exercise on insulin regulation in the Goto-Kakizaki (GK) rat as a non-obese model of non-insulin-dependent diabetes mellitus. Wistar (W/S) and GK rats were trained 2 hours daily with the swimming exercise for 4 weeks, and then the changes in the metabolism of insulin and glucose were assessed. Body weight was markedly decreased in the exercised GK rats compare to their non-exercised counterpart, while W/S rats did not show any exercise-related changes. Glucose concentration was not changed by exercise, although impaired glucose tolerance was improved in GK rats 120 min after glucose injection. However, insulin concentration was decreased by swimming exercise as in the decrease of GSIS after running exercise. To identify the other cause for exercise-induced insulin down-regulation, the changes in the levels of key factors involved in insulin production (C-peptide) and clearance (insulin-degrading enzyme; IDE) were measured in W/S and GK rats. The C-peptide level was maintained while IDE expression increased markedly. Therefore, these results showed that insulin down-regulation induced by short-term swimming exercise likely attributes to enhanced insulin clearance via IDE over-expression than by altered insulin production.

  19. 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…

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

    PubMed Central

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

    2013-01-01

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

  1. 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.

  2. 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

  3. Demonstration of the insulin receptor in vivo in rabbits and its possible role as a reservoir for the plasma hormone.

    PubMed Central

    Zeleznik, A J; Roth, J

    1978-01-01

    Based on studies of the interaction of insulin with its receptors in vitro, we calculated that a receptor compartment should be measurable directly in vivo. For this purpose, rabbits were injected intravenously with a labeled insulin that has low affinity for receptors in combination with a radioiodinated insulin that has high affinity for receptors. Plasma concentrations of labeled insulins were measured at selected intervals after injection. Apparent volumes of distribution were calculated by extrapolation of plasma distribution were calculated by extrapolation of plasma disappearance curves; high affinity insulins consistently distributed into spaces that were two-three times greater than those of the low affinity insulins. Injections of unlabeled pork insulin before tracer insulins decreased the distribution space of the high affinity insulin in a dose-dependent manner while having little or no effect on the distribution space of the low affinity labeled insulin. When unlabeled insulin was injected after the tracer insulins, there was an immediate rise in the plasma concentration of the high affinity insulin with only a slight change in the plasma concentration of the low affinity insulin. These results demonstrate that high affinity insulins distribute into a body compartment which has many properties of the insulin receptor previously studied in vitro. This receptor compartment: (a) recognizes insulins based on their biological potencies; (b) is saturated by elevated concentrations of insulin; and (c) insulin bound to receptors is in equilibrium with free hormone in plasma. Further, the bound to free ratios for hormone, calculated from these data, suggest that in vivo greater than 50% of the extrapancreatic insulin is bound to receptors during normal physiological states. PMID:659598

  4. [Insulin treatment in elder patients with diabetes].

    PubMed

    Hamaguchi, Tomoya; Namba, Mitsuyoshi

    2006-01-01

    Diabetes is a highly expanding health problem in Japan, especially for older people. The prevalence of glucose intolerance and diabetes increases with age. A postprandial hyperglycemia is the primary clinical manifestation. In older diabetic patients, atherosclerotic complications (macroangiopathies), as well as microangiopathies, are significant problems, threatening their quality of life. Though insulin therapy requires some special considerations, insulin is indicated for any patients with a poor glycemic control with oral agents. Single or multiple dose (s) of insulin injection therapy is selected for each patient to prevent symptomatic hyperglycemia, or to achieve near-normal glycemic control. Also, to maintain the quality of life for these older patients, hypoglycemia, as well as hyperglycemia, should be avoided. Newly developed insulin analogue (s) may be more appropriate for preventing hypoglycemia. Another method of prevention and treatment of hypoglycemia are discussed in this article.

  5. Insulin-induced lipohypertrophy treated by liposuction.

    PubMed

    Barak, A; Har-Shai, Y; Ullmann, Y; Hirshowitz, B

    1996-10-01

    Lipohypertrophy is one of the local side effects of repeated subcutaneous insulin injections. This case report demonstrates the successful cosmetic and therapeutic treatment of two lipohypertrophic masses in the lower abdomen of a young diabetic patient by suction-assisted lipectomy.

  6. 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

  7. 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.

  8. Treatment effects of tanshinone IIA against intracerebroventricular streptozotocin induced memory deficits in mice.

    PubMed

    Liu, Chang; Wu, Youxuan; Zha, Shuai; Liu, Mengping; Wang, Ying; Yang, Guangde; Ma, Kaige; Fei, Yulang; Zhang, Yaojie; Hu, Xiaodan; Yang, Weina; Qian, Yihua

    2016-01-15

    Our previous studies demonstrated that tanshinone IIA (tan IIA) has significant protective effects against the neurotoxicity induced by β-amyloid protein (Aβ) in cultured cortical neurons and PC12 cells. This study was designed to investigate the protective effects of tan IIA against memory deficits induced by streptozotocin (STZ) in a model of sporadic Alzheimer's disease (AD). STZ was injected twice intracerebroventrically (3mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with tan IIA (20, 40, and 80mg/kg, i.g.) starting from the first dose of STZ for 28 days showed a dose dependent improvement in STZ induced memory deficits as assessed by Morris water maze (MWM) test. Nissl staining results confirmed the protective effects of tan IIA on cerebral cortical and hippocampal neurons damage induced by STZ. In addition, tan IIA markedly reduced STZ induced elevation in acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level, and significantly inhibited STZ induced reduction in superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities in the parietal cortex and hippocampus. Moreover, tan IIA attenuated p38 mitogen activated protein kinase (MAPK) phosphorylation in the parietal cortex and hippocampus. These findings demonstrate that tan IIA prevents STZ induced memory deficits may be attributed to ameliorating neuronal damage, restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. Based on our previous studies, the present study provides further support for the potential use of tan IIA in the treatment of AD. PMID:26656068

  9. Noisy galvanic vestibular stimulation enhances spatial memory in cognitive impairment-induced by intracerebroventricular-streptozotocin administration.

    PubMed

    Adel Ghahraman, Mansoureh; Zahmatkesh, Maryam; Pourbakht, Akram; Seifi, Behjat; Jalaie, Shohreh; Adeli, Soheila; Niknami, Zohreh

    2016-04-01

    There are several anatomical connections between vestibular system and brain areas construct spatial memory. Since subliminal noisy galvanic vestibular stimulation (GVS) has been demonstrated to enhance some types of memory, we speculated that application of noisy GVS may improve spatial memory in a rat model of intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive impairment. Moreover, we attempted to determine the effect of repeated exposure to GVS on spatial memory performance. The spatial memory was assessed using Morris water maze test. The groups received 1 (ICV-STZ/GVS-I) or 5 (ICV-STZ/GVS-II) sessions, each lasting 30 min, of low amplitude noisy GVS, or no GVS at all (Control, ICV-saline, ICV-STZ/noGVS). Hippocampal morphological changes investigated with cresyl violet staining and the immediate early gene product c-Fos, as a neuronal activity marker, was measured. Hippocampal c-Fos positive cells increased in both GVS stimulated groups. We observed significantly improved spatial performance only in ICV-STZ/GVS-II group. Histological evaluation showed normal density in ICV-STZ/GVS-II group whereas degeneration observed in ICV-STZ/GVS-I group similar to ICV-STZ/noGVS. The results showed the improvement of memory impairment after repeated exposure to GVS. This effect may be due in part to frequent activation of the vestibular neurons and the hippocampal regions connected to them. Our current study suggests the potential role of GVS as a practical method to combat cognitive decline induced by sporadic Alzheimer disease.

  10. 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.

  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. 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. PMID:26586008

  13. Adalimumab Injection

    MedlinePlus

    ... not improved when treated with other medications, ulcerative colitis (a condition which causes swelling and sores in ... adalimumab injection to treat Crohn's disease or ulcerative colitis, your doctor may tell you to inject the ...

  14. Denosumab Injection

    MedlinePlus

    ... Denosumab injection (Prolia) is also used to treat bone loss in men with prostate cancer and in women with breast cancer who are receiving certain treatments that increase their risk for fractures. Denosumab injection ( ...

  15. Diphenhydramine Injection

    MedlinePlus

    ... the nervous system that causes difficulties with movement, muscle control, and balance). Diphenhydramine injection should not be ... solution (liquid) to be injected intramuscularly (into a muscle) or intravenously (into a vein). Your dosing schedule ...

  16. Leucovorin Injection

    MedlinePlus

    ... red blood cells) caused by low levels of folic acid in the body. Leucovorin injection is also used ... injection is in a class of medications called folic acid analogs. It treats people who are receiving methotrexate ...

  17. Glatiramer Injection

    MedlinePlus

    ... course of disease where symptoms flare up from time to time) of multiple sclerosis (MS; a disease in which ... to inject glatiramer, inject it around the same time every day. Follow the directions on your prescription ...

  18. Naltrexone Injection

    MedlinePlus

    Naltrexone injection is used along with counseling and social support to help people who have stopped drinking large ... injection is also used along with counseling and social support to help people who have stopped abusing opiate ...

  19. 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 ...

  20. Cefazolin Injection

    MedlinePlus

    Cefazolin injection is also sometimes used for certain penicillin allergic patients who have a heart condition and ... injection is also sometimes used to treat certain penicillin allergic women who are in labor in order ...

  1. Paclitaxel Injection

    MedlinePlus

    ... with other medications. Paclitaxel injection manufactured with polyoxyethylated castor oil is used to treat ovarian cancer (cancer that ... cancer, and lung cancer. Paclitaxel injection with polyoxyethylated castor oil is also used to treat Kaposi's sarcoma (a ...

  2. 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 ...

  3. Testosterone Injection

    MedlinePlus

    ... Testopel) are also used to stimulate puberty in males with delayed puberty. Testosterone enanthate (Delatestryl) injection may ... to the growth, development, and functioning of the male sexual organs and typical male characteristics. Testosterone injection ...

  4. 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) ...

  5. Naloxone Injection

    MedlinePlus

    ... injection device.The automatic injection device has an electronic voice system that provides step by step directions ... of opiate withdrawal such as body aches, diarrhea, fast heart beat, fever, runny nose, sneezing, sweating, yawning, ...

  6. Cefoxitin Injection

    MedlinePlus

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

  7. Doripenem Injection

    MedlinePlus

    ... tract, kidney, and abdomen that are caused by bacteria. Doripenem injection is not approved by the Food ... medications called carbapenem antibiotics. It works by killing bacteria.Antibiotics such as doripenem injection will not work ...

  8. 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 ...

  9. Medroxyprogesterone Injection

    MedlinePlus

    ... Medroxyprogesterone subcutaneous injection is also used to treat endometriosis (a condition in which the type of tissue ... parts of the body in women who have endometriosis. Medroxyprogesterone injection is a very effective method of ...

  10. Levoleucovorin Injection

    MedlinePlus

    ... injection is used to prevent harmful effects of methotrexate (Rheumatrex, Trexall) when methotrexate is used to to treat certain types of ... people who have accidentally received an overdose of methotrexate or similar medications. Levoleucovorin injection is in a ...

  11. Vancomycin Injection

    MedlinePlus

    Vancomycin injection is used alone or in combination with other medications to treat certain serious infections such ... infections of the lungs, skin, blood, and bones. Vancomycin injection is in a class of medications called ...

  12. 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

  13. Insulin-induced lipohypertrophy: report of a case with histopathology.

    PubMed

    Fujikura, Junji; Fujimoto, Muneya; Yasue, Shintaro; Noguchi, Michio; Masuzaki, Hiroaki; Hosoda, Kiminori; Tachibana, Takao; Sugihara, Hajime; Nakao, Kazuwa

    2005-10-01

    An 82-year-old woman with type 2 diabetes had been treated with recombinant human insulin for 16 years. She developed large swellings in both sides of her lower abdomen. The masses were soft, painless, and located around her insulin injection sites. Based on the history and clinical features, a diagnosis of insulin-induced lipohypertrophy was made. Total resection revealed that the lesions were composed entirely of fatty tissue. Microscopic examination showed nests of mature adipocytes expanding toward the dermal reticular layer. The hypertrophic adipocytes were twice as large as those from normal subcutaneous areas and contained numerous small lipid droplets. Electron microscopic analysis also revealed a minor population of small adipocytes, suggesting active differentiation or proliferation. Thus, the possible in vivo effects of insulin on adipocytes were clearly observed in this case of insulin-induced lipohypertrophy. To our knowledge, this is the first report of insulin-induced lipohypertrophy with detailed histological examinations.

  14. Choosing injectable therapy: The metabolic fulcrum.

    PubMed

    Kalra, Sanjay; Gupta, Yashdeep

    2016-07-01

    This clinical decision making hypothesis utilizes the metabolic fulcrum based approach to classify persons with diabetes into three categories: predominantly catabolic, eubolic, and predominantly [maladaptive] anabolic. This systematic arrangement helps define choice of injectable therapy in type 2 diabetes mellitus. Patients with predominant catabolism, may respond better to intensive insulin therapy. Dual action insulin, including premixed insulin and I Deg Asp (insulin degludec aspart), may be an acceptable alternative. Uncomplicated, eumetabolic patients with type 2 diabetes may use any of the various drugs available. Patients classified as having maladaptive anabolism may benefit from a GLP1RA. If this does not suffice, a GLP1RA + basal insulin combination may be effective. PMID:27427149

  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. The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats.

    PubMed

    Liu, Xin-Feng; Fawcett, John R; Hanson, Leah R; Frey, William H

    2004-01-01

    Intracerebroventricular injection of insulin-like growth factor (IGF)-I has been shown to protect against stroke in rats. This method of delivery is not practical in human beings, as it requires an operation with risk of infection and other complications. Intranasal (i.n.) delivery offers a noninvasive method of bypassing the blood-brain barrier to deliver IGF-I to the brain. This study delineates the window of opportunity for treatment of focal cerebral ischemic damage using i.n. IGF-I after middle cerebral artery occlusion (MCAO). Rats were allowed to survive 7 days after 2 hours of MCAO. Infarct volume, apoptosis after 7 days, and neurologic deficit scores from the postural reflex and adhesive tape tests assessing motor-sensory and somatosensory functions, respectively, at 1 to 7 days were used to evaluate the efficacy of i.n. IGF-I (150 microg) administered at different times after MCAO. I.n. IGF-I significantly reduced infarct volume by 54%; and 39%; versus control when administered at 2 or 4 hours, respectively, after the onset of MCAO (P < .05) and improved motor-sensory and somatosensory functions (P < .05) when administered 2 hours after the onset of MCAO. In addition, treatment with i.n. IGF-I at 2, 4, or 6 hours after MCAO decreased apoptotic cell counts by more than 90%; in the hemisphere ipsilateral to the occlusion. I.n. IGF-I is a promising treatment for stroke with a therapeutic window of opportunity for up to 6 hours after the onset of ischemia. This noninvasive method provides a simpler, safer, and potentially more cost-effective method of delivery than other methods currently in use.

  17. Insulin Human Inhalation

    MedlinePlus

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

  18. 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 ...

  19. High-mix insulins

    PubMed Central

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

    2015-01-01

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

  20. Insulin, insulin analogues and diabetic retinopathy.

    PubMed

    Chantelau, Ernst; Kimmerle, Renate; Meyer-Schwickerath, Rolf

    2008-02-01

    Insulin is absolutely vital for living beings. It is not only involved in metabolism, but also in the regulation of growth factors, e.g. IGF-1. In this review we address the role insulin has in the natural evolution of diabetic retinopathy. On the one hand, chronic deficiency of insulin and IGF-1 at the retina is thought to cause capillary degeneration, with subsequent ischaemia. On the other hand, acute abundance of (exogenously administered) insulin and IGF-1 enhances ischaemia-induced VEGF expression. A critical ratio of tissue VEGF-susceptibility: VEGF-availability triggers vascular proliferation (i.e. of micro-aneurysms and/or abnormal vessels). The patent-protected insulin analogues Lispro, Glulisine, Aspart, Glargine and Detemir are artificial insulin derivatives with altered biological responses compared to natural insulin (e.g. divergent insulin and /or IGF-1 receptor-binding characteristics, signalling patterns, and mitogenicity). Their safety profiles concerning diabetic retinopathy remain to be established by randomised controlled trials. Anecdotal reports and circumstantial evidence suggest that Lispro and Glargine might worsen diabetic retinopathy.

  1. Adherence to Insulin Therapy.

    PubMed

    Sarbacker, G Blair; Urteaga, Elizabeth M

    2016-08-01

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

  2. 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.

  3. Insulin therapy in pregnancy.

    PubMed

    Kalra, Sanjay; Jawad, Fatema

    2016-09-01

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

  4. Investigations into the absorption of insulin and insulin derivatives from the small intestine of the anaesthetised rat.

    PubMed

    McGinn, B J; Morrison, J D

    2016-06-28

    Experiments have been undertaken to determine the extent to which cholic acid conjugates of insulin were absorbed from the small intestine of anaesthetised rats by means of the bile salt transporters of the ileum. The measure used to assess the absorption of the cholyl-insulins was the amount of hypoglycaemia following infusion into the small intestine. Control experiments involving infusion of natural insulin into the ileum showed either nil absorption or absorption of a small amount of insulin as indicated by transient dip in the blood glucose concentration. However, when insulin was co-infused with the bile salt taurocholate, this was followed by a marked hypoglycaemic response which was specific to the ileum and did not occur on infusion into the jejunum. When the two cholyl conjugates of insulin were tested viz. B(29)-Lys-cholyl-insulin and B(1)-Phe-cholyl-insulin, both were biologically active as indicated by hypoglycaemic responses on systemic injection, though their potency was about 40% of that of natural insulin. While there was no evidence for the absorption of B(29)-Lys-cholyl-insulin when infused into the ileum, B(1)-Phe-cholyl-insulin did cause a long lasting hypoglycaemic response, indicating that absorption had occurred. Since the hypoglycaemic response was blocked on co-infusion with taurocholate and was absent for infusion of the conjugate into the jejunum, these results were taken as evidence that B(1)-Phe-cholyl-insulin had been taken up by the ileal bile salt transporters. This would indicate that B(1)-Phe-cholyl-insulin is worthy of further investigation for use in an oral insulin formulation.

  5. Noisy galvanic vestibular stimulation enhances spatial memory in cognitive impairment-induced by intracerebroventricular-streptozotocin administration.

    PubMed

    Adel Ghahraman, Mansoureh; Zahmatkesh, Maryam; Pourbakht, Akram; Seifi, Behjat; Jalaie, Shohreh; Adeli, Soheila; Niknami, Zohreh

    2016-04-01

    There are several anatomical connections between vestibular system and brain areas construct spatial memory. Since subliminal noisy galvanic vestibular stimulation (GVS) has been demonstrated to enhance some types of memory, we speculated that application of noisy GVS may improve spatial memory in a rat model of intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive impairment. Moreover, we attempted to determine the effect of repeated exposure to GVS on spatial memory performance. The spatial memory was assessed using Morris water maze test. The groups received 1 (ICV-STZ/GVS-I) or 5 (ICV-STZ/GVS-II) sessions, each lasting 30 min, of low amplitude noisy GVS, or no GVS at all (Control, ICV-saline, ICV-STZ/noGVS). Hippocampal morphological changes investigated with cresyl violet staining and the immediate early gene product c-Fos, as a neuronal activity marker, was measured. Hippocampal c-Fos positive cells increased in both GVS stimulated groups. We observed significantly improved spatial performance only in ICV-STZ/GVS-II group. Histological evaluation showed normal density in ICV-STZ/GVS-II group whereas degeneration observed in ICV-STZ/GVS-I group similar to ICV-STZ/noGVS. The results showed the improvement of memory impairment after repeated exposure to GVS. This effect may be due in part to frequent activation of the vestibular neurons and the hippocampal regions connected to them. Our current study suggests the potential role of GVS as a practical method to combat cognitive decline induced by sporadic Alzheimer disease. PMID:26892259

  6. Antinociceptive effect of intracerebroventricular administration of glycine transporter-2 inhibitor ALX1393 in rat models of inflammatory and neuropathic pain.

    PubMed

    Takahashi, Yoshihiro; Hara, Koji; Haranishi, Yasunori; Terada, Tadanori; Obara, Goh; Sata, Takeyoshi

    2015-03-01

    Glycinergic transmission has an important role in regulating nociception in the spinal cord. The glycine transporter-2 (GlyT2) is localized at presynaptic terminals of glycinergic neurons and eliminates glycine from the synaptic cleft to terminate glycinergic transmission. Systemic and intrathecal administration of GlyT2 inhibitors alleviate various types of pain. Although the GlyT2s and glycine receptors are widely distributed in the central nervous system, little is known about the role of glycinergic transmission in pain perception at supraspinal regions. The present study examined the antinociceptive effect of intracerebroventricular (i.c.v.) administration of the selective GlyT2 inhibitor ALX1393 on inflammatory and neuropathic pain in experimental models. For i.c.v. administration, a guide cannula was implanted into the right lateral ventricle of male Sprague-Dawley rats. Normal rats were used to assess inflammatory nociception using the formalin test and motor function using the rotarod test. Chronic constriction injury (CCI) to the sciatic nerve was induced in the rats. The CCI rats were then used to assess mechanical, cold, and thermal hyperalgesia using the electronic von Frey test, cold plate test, and the plantar test, respectively. ALX1393 (25, 50, and 100 μg) was administered i.c.v. to examine its effects on supraspinal antinociception. Supraspinal ALX1393 in normal rats suppressed the late-phase response in the formalin test but did not affect motor performance. In the CCI rats, ALX1393 inhibited mechanical and cold hyperalgesia in a dose-dependent manner. The antihyperalgesic effects of ALX1393 (100 μg) were reversed completely by i.c.v. pretreatment with a glycine receptor antagonist strychnine (10 μg). These results suggest that GlyT2 contributes to nociceptive transmission at supraspinal level and that the selective GlyT2 inhibitor is a promising candidate for the treatment of inflammatory and neuropathic pain without causing motor dysfunction

  7. Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist.

    PubMed

    Coleman, Brian R; Carlezon, William A; Myers, Karyn M

    2013-04-29

    Maladaptive conditioned responses (CRs) contribute to psychiatric disorders including anxiety disorders and addiction. Methods of reducing these CRs have been considered as possible therapeutic approaches. One such method is extinction, which involves exposure to CR-eliciting cues in the absence of the event they once predicted. In animal models, extinction reduces both fear and addiction-related CRs, and in humans, extinction-based cue exposure therapy (CET) reduces fear CRs. However, CET is less effective in drug addicts, for reasons that are not clear. Increased understanding of the neurobiology of extinction of drug-related CRs as compared to fear CRs may help illuminate this issue. Here, we examine the N-methyl-d-aspartate (NMDA) receptor-dependence of extinction of conditioned opiate withdrawal in rats. Using a place conditioning paradigm, we trained morphine-dependent rats to associate an environment with naloxone-precipitated withdrawal. We then extinguished that association by returning the rats repeatedly to the environment in the absence of acute withdrawal. In some rats we administered the NMDA receptor antagonist d,l-2-amino-5-phosphovaleric acid (AP5) intracerebroventricularly immediately prior to extinction training. In a subsequent test session, these rats avoided the formerly naloxone-paired environment, similar to rats that had not undergone extinction training. By contrast, rats that received vehicle prior to extinction training did not avoid the formerly naloxone-paired environment. This finding indicates that extinction of a drug-related CR (conditioned opiate withdrawal) is dependent on NMDA receptors, similar to extinction of conditioned fear. The locus of the critical NMDA receptors is unclear but may include basolateral amygdala and/or medial prefrontal cortex. PMID:23416323

  8. 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. PMID:26954230

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

    PubMed Central

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

    2016-01-01

    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. PMID:26954230

  10. 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

  11. 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

  12. Addendum 2: Forum for Injection Technique, India

    PubMed Central

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

    2014-01-01

    The second addendum to the Forum for Injection Techniques (FIT), India recommendations, first published in 2012 and followed by an addendum in 2013, covers various important issues. It describes how the impact of the so-called non-modifiable factors, which influence the injection technique, can be modulated; provides fresh information on timing of glucagon-like peptide 1 receptor agonist injections, methods of minimizing pain during injections, amyloidosis, and factors that impact adherence to insulin therapy. The addendum also lists semantic changes made to keep the FIT recommendations updated.

  13. Heterogeneous distribution of 125I-insulin binding sites in the liver of fed and fasted mice.

    PubMed

    Nakanishi, M; Watanabe, M; Shimada, M

    1995-02-01

    A microradioautography made three min. after intravenous injection of 125I-insulin was used to study the distribution of insulin binding sites in the liver of fed and fasted mice. A substantial specific binding of 125I-insulin to liver parenchymal cells could be seen in these mice, whereas radioautographs from animals injected with 125I-insulin plus an excess of unlabelled insulin showed only trace amounts of silver grains. In both fed and fasted mice, a density gradient of the binding from the periportal zone to the perivenous zone was evident, and the binding in each zone was significantly higher in the fasted mice than in the fed mice.

  14. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling

    PubMed Central

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V.

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling. PMID:27537838

  15. Preserved Na/HCO3 cotransporter sensitivity to insulin may promote hypertension in metabolic syndrome.

    PubMed

    Nakamura, Motonobu; Yamazaki, Osamu; Shirai, Ayumi; Horita, Shoko; Satoh, Nobuhiko; Suzuki, Masashi; Hamasaki, Yoshifumi; Noiri, Eisei; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George

    2015-03-01

    Hyperinsulinemia can contribute to hypertension through effects on sodium transport. To test whether the stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in insulin resistance, we compared the effects of insulin on abdominal adipocytes and proximal tubules in rats and humans. Insulin markedly stimulated the sodium-bicarbonate cotransporter (NBCe1) activity in isolated proximal tubules through the phosphoinositide 3-kinase (PI3-K) pathway. Gene silencing in rats showed that while insulin receptor substrate (IRS)1 mediates the insulin effect on glucose uptake into adipocytes, IRS2 mediates the insulin effect on proximal tubule transport. The stimulatory effect of insulin on glucose uptake into adipocytes was severely reduced, but its stimulatory effect on NBCe1 activity was completely preserved in insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats and patients with insulin resistance. Despite widespread reduction of IRS1 and IRS2 expression in insulin-sensitive tissues, IRS2 expression in the kidney cortex was exceptionally preserved in both OLETF rats and patients with insulin resistance. Unlike liver, acute insulin injection failed to change the expression levels of IRS2 and sterol regulatory element-binding protein 1 in rat kidney cortex, indicating that regulatory mechanisms of IRS2 expression are distinct in liver and kidney. Thus, preserved stimulation of proximal tubule transport through the insulin/IRS2/PI3-K pathway may play an important role in the pathogenesis of hypertension associated with metabolic syndrome.

  16. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    PubMed

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling. PMID:27537838

  17. Ultrasound-triggered regulation of blood glucose levels using injectable nano-network.

    PubMed

    Di, Jin; Price, Jennifer; Gu, Xiao; Jiang, Xiaoning; Jing, Yun; Gu, Zhen

    2014-06-01

    The integration of an injectable insulin-encapsulated nano-network with a focused ultrasound system (FUS) can remotely regulate insulin release both in vitro and in vivo. A single subcutaneous injection of the nano-network with intermittent FUS administration facilitates reduction of the blood glucose levels in type 1 diabetic mice for up to 10 d. PMID:24255016

  18. Retrospective evaluation of continuous rate infusion of regular insulin intravenously for the management of feline diabetic ketoacidosis.

    PubMed

    Bollinger, Pamela N; Moore, Lisa E

    2015-01-01

    The use and efficacy of continuous rate infusion (CRI) of regular insulin intravenously for the treatment of feline diabetic ketoacidosis was retrospectively evaluated. The study focused on the rate of glucose decline, time to resolution of inappetence, time to long-term injectable insulin, and length of hospital stay. Review of medical records from 2009 to 2011 identified 10 cases that met the inclusion criteria. Six cats were existing diabetics, 3 of whom had recent insulin changes. Five cats had concurrent diseases. The mean time to long-term injectable insulin was 55 hours. The mean length of hospitalization was 3.8 days. Five cats survived to discharge. In 5 patients, an insulin CRI permitted a short hospital stay and transition to long-term injectable insulin. Many cats with diabetic ketosis or diabetic ketoacidosis are prior diabetics with concurrent disease and/or a history of recent insulin changes.

  19. The Role of Hypothalamic mTORC1 Signaling in Insulin Regulation of Food Intake, Body Weight, and Sympathetic Nerve Activity in Male Mice

    PubMed Central

    Muta, Kenjiro; Morgan, Donald A.

    2015-01-01

    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. PMID:25574706

  20. Lipohypertrophy and lipoatrophy complicating treatment with highly purified bovine and porcine insulins.

    PubMed

    McNally, P G; Jowett, N I; Kurinczuk, J J; Peck, R W; Hearnshaw, J R

    1988-11-01

    Lipoatrophy and lipohypertrophy were the most frequently reported local complications of conventional insulin therapy. Early reports following the introduction of highly purified insulins suggested a reduction in the frequency of lipohypertrophy and lipoatrophy. Since highly purified insulins have been in common usage for 10 years, the present frequency of these complications was assessed in a study of 281 insulin treated diabetics. Lipohypertrophy was recorded in 76 (27.1%) patients including 3 with associated lipoatrophy. Lipoatrophy was found in 7 (2.5%) cases (3 porcine and 4 bovine insulin treated), 4 of which had only ever used highly purified insulins. Despite the introduction of highly purified insulins, lipohypertrophy and lipoatrophy remain prevalent in insulin treated patients. This common complication may be limited by routinely inspecting injection sites.

  1. Triptorelin Injection

    MedlinePlus

    ... response to triptorelin injection. Your blood sugar and glycosylated hemoglobin (HbA1c) should be checked regularly.Ask your pharmacist any questions you have about triptorelin injection.It is important for you to keep a written list of all of the prescription and ...

  2. Leuprolide Injection

    MedlinePlus

    ... response to leuprolide injection. Your blood sugar and glycosylated hemoglobin (HbA1c) should be checked regularly.Ask your pharmacist any questions you have about leuprolide injection.It is important for you to keep a written list of all of the prescription and ...

  3. 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

  4. 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

  5. Effects of intracerebroventricular administration of ultra low doses of histaminergic drugs on morphine state-dependent memory of passive avoidance in mice.

    PubMed

    Khalilzadeh, Azita; Zarrindast, Mohammad-Reza; Djahanguiri, Bijan

    2006-01-01

    The effects of intracerebroventricular (i.c.v.) administration of ultra low doses (ULDs) of histamine, clobenpropit and pyrilamine are studied on morphine state-dependent (STD) memory in mice. Although pre-test administration of different doses of histamine and clobenpropit showed no effect on impairment of memory induced by pre-training morphine, when the above drugs were co-administered with morphine, they inhibited the restoration of memory by morphine. These effects were opposite to microgram doses of the same drugs.

  6. 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

  7. Tea enhances insulin activity.

    PubMed

    Anderson, Richard A; Polansky, Marilyn M

    2002-11-20

    The most widely known health benefits of tea relate to the polyphenols as the principal active ingredients in protection against oxidative damage and in antibacterial, antiviral, anticarcinogenic, and antimutagenic activities, but polyphenols in tea may also increase insulin activity. The objective of this study was to determine the insulin-enhancing properties of tea and its components. Tea, as normally consumed, was shown to increase insulin activity >15-fold in vitro in an epididymal fat cell assay. Black, green, and oolong teas but not herbal teas, which are not teas in the traditional sense because they do not contain leaves of Camellia senensis, were all shown to increase insulin activity. High-performance liquid chromatography fractionation of tea extracts utilizing a Waters SymmetryPrep C18 column showed that the majority of the insulin-potentiating activity for green and oolong teas was due to epigallocatechin gallate. For black tea, the activity was present in several regions of the chromatogram corresponding to, in addition to epigallocatechin gallate, tannins, theaflavins, and other undefined compounds. Several known compounds found in tea were shown to enhance insulin with the greatest activity due to epigallocatechin gallate followed by epicatechin gallate, tannins, and theaflavins. Caffeine, catechin, and epicatechin displayed insignificant insulin-enhancing activities. Addition of lemon to the tea did not affect the insulin-potentiating activity. Addition of 5 g of 2% milk per cup decreased the insulin-potentiating activity one-third, and addition of 50 g of milk per cup decreased the insulin-potentiating activity approximately 90%. Nondairy creamers and soy milk also decreased the insulin-enhancing activity. These data demonstrate that tea contains in vitro insulin-enhancing activity and the predominant active ingredient is epigallocatechin gallate. PMID:12428980

  8. The chronic intracerebroventricular infusion of interleukin-1 beta alters the activity of the hypothalamic-pituitary-gonadal axis of cycling rats. II. Induction of pseudopregnant-like corpora lutea.

    PubMed

    Rivier, C; Erickson, G

    1993-12-01

    The acute administration of interleukin-1 beta (IL-1 beta) into the brain ventricles of rats has been shown to cause a significant decrease in plasma LH levels, a phenomenon primarily mediated through inhibition of LHRH release. However, there are no studies of the long-term consequences of IL-1 beta injected intracerebroventricularly on the hypothalamic-pituitary-gonadal axis. In particular, we became interested in determining whether IL-1 beta exerts deleterious effects on reproductive parameters, and to what extent they might be caused by a lowering of circulating gonadotropins. In the present experiments, we therefore investigated the effects of the infusion of IL-1 beta to intact cycling female rats and compared them to those observed in rats injected with a potent LHRH antagonist. Although blockade of LHRH receptors caused a modest and delayed inhibition of progesterone secretion, infusion of IL-1 beta (4 ng/h for 4-6 days) was accompanied by persistent and significant increases in plasma P4 levels. In these rats, the PRL release was erratic, with low values during the morning and generally extremely elevated values during the night. The volume of the corpora lutea-I (CL-I) of rats exposed to IL-1 beta, but not to the vehicle or the LHRH antagonist, was significantly increased, and the lutein cells showed extensive hypertrophy. These results indicate that prolonged infusion of IL-1 beta into the brain of cycling rats blocks luteolysis in newly formed CL. These changes were not present in rats injected with the LHRH antagonist, suggesting that they were not primarily related to decreases in gonadotropin secretion. We propose that the high plasma PRL levels may play a role in the changes in ovarian activity which we observed, through other mechanisms, such as sustained increases in adrenal epinephrine and/or glucocorticoids, may also be involved. These findings indicate a novel role for central IL-1 beta in the prevention of luteolysis and the transformation of

  9. [Delayed hypersensitivity to protamine and immediate hypersensitivity to insulin].

    PubMed

    Köllner, A; Senff, H; Engelmann, L; Kalveram, K J; Velcovsky, H G; Haneke, E

    1991-08-16

    A 63-year-old female, with type II diabetes mellitus, diagnosed in 1967, was started on combination therapy with sulphonylureas and human depot insulin in May 1989, because of inadequate blood sugar control with sulphonylureas alone. Within 3 months she began to develop nodular skin reactions at the site of injection, 12-24 hours after insulin injections. Intradermal testing demonstrated delayed (Gell and Coombs type IV) hypersensitivity to protamine. No specific IgE or IgG antibodies were demonstrable. She was changed to protamine-free human delayed action insulin. After an initial reaction-free period, red urticarial lesions, attributable to immediate (Gell and Coombs type I) hypersensitivity to human insulin, appeared at the injection sites. There were no other complications with continued insulin therapy, and after about 6 weeks no further local reactions were detectable. When an allergic reaction to an insulin preparation is suspected, careful immunological investigation should be performed, to ensure adequate treatment without risk to the patient.

  10. The Role of Comfort and Discomfort in Insulin Therapy

    PubMed Central

    2012-01-01

    Abstract Despite the recognized importance of optimal insulin therapy, patient adherence to insulin therapy is an ongoing clinical care challenge. Insulin omission continues to be frequent and underestimated and has been correlated with poorer glycemic control and increased rates of diabetes-related complications. Insulin users consistently indentify multiple factors that contribute to insulin injection-related anxiety and to non-adherence. Injection-related discomfort continues to bear a significant contribution. Over the last decade, with advances in needle manufacturing technology, shorter and narrower needles have been associated with progressively improving patient self-rating of injection discomfort. Consequently, patient surveys of insulin users show discomfort to rank in the bottom third of significant contributors by prevalence. However, healthcare providers (HCP) and family member care providers continue to demonstrate a high level of anticipated and perceived pain for the patient. HCP anxiety and pain anticipation are each associated with patient anxiety and may therefore play a significant contributing role in patient non-adherence. PMID:22537418

  11. Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes

    PubMed Central

    German, Jonathan P.; Wisse, Brent E.; Thaler, Joshua P.; Oh-I, Shinsuke; Sarruf, David A.; Ogimoto, Kayoko; Kaiyala, Karl J.; Fischer, Jonathan D.; Matsen, Miles E.; Taborsky, Gerald J.; Schwartz, Michael W.; Morton, Gregory J.

    2010-01-01

    OBJECTIVE Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS Adult male Wistar rats remained nondiabetic or were injected with the β-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 μg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine

  12. Mipomersen Injection

    MedlinePlus

    ... the refrigerator at least 30 minutes before you plan to inject it to allow the medication to ... supplements, and herbal products you are taking or plan to take. Be sure to mention the medications ...

  13. 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 ...

  14. Romiplostim Injection

    MedlinePlus

    ... including other medications or surgery to remove the spleen. Romiplostim injection should not be used to treat ... tell your doctor if you have had your spleen removed.tell your doctor if you are pregnant, ...

  15. Golimumab Injection

    MedlinePlus

    ... and swelling and scales on the skin). ulcerative colitis (a condition which causes swelling and sores in ... you are using golimumab injection to treat ulcerative colitis (a condition which causes swelling and sores in ...

  16. Colistimethate Injection

    MedlinePlus

    ... antibiotics. It works by killing bacteria that cause infection.Antibiotics such as colistimethate injection will not work for colds, flu, or other viral infections. Taking or using antibiotics when they are not needed increases your risk ...

  17. Doxycycline Injection

    MedlinePlus

    ... antibiotics. It works by killing bacteria that cause infections.Antibiotics such as doxycycline injection will not work for colds, flu, or other viral infections. Taking or using antibiotics when they are not needed increases your risk ...

  18. Tigecycline Injection

    MedlinePlus

    ... in a person who was not in the hospital), skin infections, and infections of the abdomen (area between the ... that developed in people who were in a hospital or foot infections in people who have diabetes. Tigecycline injection is ...

  19. Thiotepa Injection

    MedlinePlus

    ... reproductive organs where eggs are formed), breast, and bladder cancer. It is also used to treat malignant effusions ( ... how you respond to thiotepa.When used for bladder cancer, thiotepa is infused (injected slowly) into your bladder ...

  20. Ferumoxytol Injection

    MedlinePlus

    Ferumoxytol injection is used to treat iron-deficiency anemia (a lower than normal number of red blood cells due to too little iron) in adults with chronic kidney disease (damage to the kidneys which may worsen over ...

  1. 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. ...

  2. Olanzapine Injection

    MedlinePlus

    Olanzapine extended-release injection is used to treat schizophrenia (a mental illness that causes disturbed or unusual ... treat episodes of agitation in people who have schizophrenia or in people who have bipolar I disorder ( ...

  3. 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 ...

  4. Acetaminophen Injection

    MedlinePlus

    ... injection is also used in combination with opioid (narcotic) medications to relieve moderate to severe pain. Acetaminophen is in a class of medications called analgesics (pain relievers) and antipyretics (fever reducers). It works by changing ...

  5. 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 ...

  6. Dolasetron Injection

    MedlinePlus

    Dolasetron injection is used to prevent and treat nausea and vomiting that may occur after surgery. Dolasetron ... should not be used to prevent or treat nausea and vomiting in people receiving cancer chemotherapy medications. ...

  7. Teduglutide Injection

    MedlinePlus

    ... syndrome in people who need additional nutrition or fluids from intravenous (IV) therapy. Teduglutide injection is in ... analogs. It works by improving the absorption of fluids and nutrients in the intestines.

  8. 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, ...

  9. 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, ...

  10. 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, ...

  11. Lacosamide Injection

    MedlinePlus

    ... drowsiness uncontrollable shaking of a part of the body problems with coordination, balance, or walking weakness itching redness, irritation, pain, or discomfort at the injection spot Some side effects can be serious. If you experience any of ...

  12. Epinephrine Injection

    MedlinePlus

    ... emergency medical treatment to treat life-threatening allergic reactions caused by insect bites or stings, foods, medications, ... at the first sign of a serious allergic reaction.Use epinephrine injection exactly as directed; do not ...

  13. 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, ...

  14. 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. ...

  15. Bendamustine Injection

    MedlinePlus

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

  16. 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 ...

  17. 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 ...

  18. 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 ...

  19. 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 ...

  20. 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 ...

  1. 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 ...

  2. Telavancin Injection

    MedlinePlus

    ... serious skin infections caused by certain types of bacteria. Telavancin injection is in a class of medications ... antibiotics. It works by stopping the growth of bacteria. Antibiotics will not work for colds, flu, or ...

  3. 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, ...

  4. 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, ...

  5. 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 ...

  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. Ciprofloxacin Injection

    MedlinePlus

    ... Ciprofloxacin injection is also sometimes used to treat cat scratch disease (an infection that may develop after a person is bitten or scratched by a cat), Legionnaires' disease (type of lung infection), and infections of the ...

  9. Ganciclovir Injection

    MedlinePlus

    Ganciclovir injection is used to treat cytomegalovirus (CMV) retinitis (eye infection that can cause blindness) in people whose immune system is not working normally, including those people who have ...

  10. Levofloxacin Injection

    MedlinePlus

    ... infections. Levofloxacin injection is also used to prevent anthrax (a serious infection that may be spread on ... in people who may have been exposed to anthrax germs in the air and treat and prevent ...

  11. Ibandronate Injection

    MedlinePlus

    ... Ibandronate is in a class of medications called bisphosphonates. It works by preventing bone breakdown and increasing ... while receiving this medication.Being treated with a bisphosphonate medication such as ibandronate injection for osteoporosis may ...

  12. Fondaparinux Injection

    MedlinePlus

    ... the leg), which can lead to pulmonary embolism (PE; a blood clot in the lung), in people ... with warfarin (Coumadin, Jantoven) to treat DVT or PE. Fondaparinux injection is in a class of medications ...

  13. Pertuzumab Injection

    MedlinePlus

    ... docetaxel (Taxotere) to treat a certain type of breast cancer that has spread to other parts of the body. Pertuzumab injection is in a class of medications called monoclonal antibodies. It works by stopping the growth of cancer ...

  14. Octreotide Injection

    MedlinePlus

    ... injection is used to decrease the amount of growth hormone (a natural substance) produced by people with acromegaly (condition in which the body produces too much growth hormone, causing enlargement of the hands, feet, and facial ...

  15. Haloperidol Injection

    MedlinePlus

    ... release injection are used to treat schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of ... medications); medications for anxiety, depression, irritable bowel disease, mental illness, motion sickness, Parkinson's disease, seizures, ulcers, or urinary ...

  16. 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). ...

  17. 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 ...

  18. Pembrolizumab Injection

    MedlinePlus

    ... treat a certain type of non-small-cell lung cancer that has spread to nearby tissues or to ... successfully with other medications for non-small-cell lung cancer. Pembrolizumab injection is in a class of medications ...

  19. Oritavancin Injection

    MedlinePlus

    ... for at least 5 days after receiving oritavancin injection.tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking ...

  20. Cefuroxime Injection

    MedlinePlus

    ... pneumonia and other lower respiratory tract (lung) infections; meningitis (infection of the membranes that surround the brain ... hearing loss, if you are being treated for meningitis Cefuroxime injection may cause other side effects. Call ...

  1. Alirocumab Injection

    MedlinePlus

    ... further decrease the amount of low-density lipoprotein (LDL) cholesterol ('bad cholesterol') in the blood. Alirocumab injection is ... antibodies. It works by blocking the production of LDL cholesterol in the body to decrease the amount of ...

  2. Secukinumab Injection

    MedlinePlus

    ... to see if you need to receive any vaccinations. It is important to have all vaccines appropriate ... treatment with secukinumab injection. Do not have any vaccinations during your treatment without talking to your doctor. ...

  3. Pathophysiology of insulin secretion.

    PubMed

    Scheen, A J

    2004-02-01

    Defects in pancreatic islet beta-cell function play a major role in the development of diabetes mellitus. Type 1 diabetes is caused by a more or less rapid destruction of pancreatic beta cells, and the autoimmune process begins years before the beta-cell destruction becomes complete, thereby providing a window of opportunity for intervention. During the preclinical period and early after diagnosis, much of the insulin deficiency may be the result of functional inhibition of insulin secretion that may be at least partially and transiently reversible. Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial (probably of genetic origin) defect in acute or first-phase insulin secretion, followed by a decreasing maximal capacity of insulin secretion. Last, a defective steady-state and basal insulin secretion develops, leading to almost complete beta-cell failure requiring insulin treatment. Because of the reciprocal relation between insulin secretion and insulin sensitivity, valid representation of beta-cell function requires interpretation of insulin responses in the context of the prevailing degree of insulin sensitivity. This appropriate approach highlights defects in insulin secretion at the various stages of the natural history of type 2 diabetes and already present in individuals at risk to develop the disease. To date none of the available therapies can stop the progressive beta-cell defect and the progression of the metabolic disorder. The better understanding of the pathophysiology of the disease should lead to the development of new strategies to preserve beta-cell function in both type 1 and type 2 diabetes mellitus.

  4. Importance of transcapillary insulin transport on insulin action in vivo

    SciTech Connect

    Yang, Y.J.

    1989-01-01

    The relationship between transcapillary insulin transport and insulin action was examined in normal conscious dogs. Plasma and thoracic duct lymph insulin, and insulin action were simultaneously measured during euglycemic clamps and intravenous glucose tolerance tests. During the clamps, while {sup 14}C-inulin reached an equilibrium, steady-state (ss) plasma insulin was higher than lymph and the ratio of 3:2 was maintained during basal, activation and deactivation phases: 18 {+-} 2 vs. 12 {+-} 1, 51 {+-} 2 vs. 32 {+-} 1, and 18 {+-} 3 vs. 13 {+-} 1 {mu}U/ml. In addition, it took longer for lymph insulin to reach ss than plasma insulin during activation and deactivation: 11 {+-} 2 vs. 31 {+-} 5 and 8 {+-} 2 vs. 32 {+-} 6 min. During IVGTT, plasma insulin peaked within 5 {+-} 2 min; lymph insulin rose slowly to a lower peak. The significant gradient and delay between plasma and lymph insulin concentrations suggest a restricted transcapillary insulin transport.

  5. Prolonged hypoglycemic effect in diabetic dogs due to subcutaneous administration of insulin in liposomes

    SciTech Connect

    Stevenson, R.W.; Patel, H.M.; Parsons, J.A.; Ryman, B.E.

    1982-06-01

    The biologic action of insulin entrapped in liposomes (phospholipid vesicles) has been investigated following subcutaneous injection to dogs made diabetic with a combination of alloxan and streptozotocin. The fate of the liposomally entrapped material was determined by injecting rats subcutaneously with either /sup 125/I-insulin or the labeled polysaccharide /sup 14/C-inulin, incorporated in liposomes labeled with /sup 3/H-cholesterol. Injection of liposome insulin (0.75 U/kg) to five diabetic dogs resulted in a mean (+/- SEM) blood glucose fall from 16.4 +/- 0.8 to 2.9 +/- 0.4 mmol/L. The glucose level had still not returned to baseline after 24 h and, correspondingly, immunoreactive insulin (IRI) could still be detected in frozen and thawed plasma 24 h after injection. In contrast, the hypoglycemic effect of the same dose of free insulin with or without empty liposomes virtually ended within 8 h and IRI levels returned to baseline by 3 h after injection. In experiments on rats with liposomally entrapped /sup 125/I-insulin or /sup 14/C-inulin the proportion of the injected dose of tracer recoverable by excision of the injection site remained constant after about 1 h and 70% of the dose was still fixed in subcutaneous tissue for at least 5 h thereafter. When the plasma collected 3 h after subcutaneous injection of labeled liposomes containing /sup 125/I-insulin was passed through a column of Sepharose 6B, 50-75% of the /sup 125/I-activity was found in the fractions associated with intact liposomes. One possibility for the persistence of the hypoglycemic effect and of measurable IRI following injection of liposome insulin could be the presence of intact liposomes in the circulation for many hours after adsorption had ceased.

  6. 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.

  7. Adipocyte Metrnl Antagonizes Insulin Resistance Through PPARγ Signaling.

    PubMed

    Li, Zhi-Yong; Song, Jie; Zheng, Si-Li; Fan, Mao-Bing; Guan, Yun-Feng; Qu, Yi; Xu, Jian; Wang, Pei; Miao, Chao-Yu

    2015-12-01

    Adipokines play important roles in metabolic homeostasis and disease. We have recently identified a novel adipokine Metrnl, also known as Subfatin, for its high expression in subcutaneous fat. Here, we demonstrate a prodifferentiation action of Metrnl in white adipocytes. Adipocyte-specific knockout of Metrnl exacerbates insulin resistance induced by high-fat diet (HFD), whereas adipocyte-specific transgenic overexpression of Metrnl prevents insulin resistance induced by HFD or leptin deletion. Body weight and adipose content are not changed by adipocyte Metrnl. Consistently, no correlation is found between serum Metrnl level and BMI in humans. Metrnl promotes white adipocyte differentiation, expandability, and lipid metabolism and inhibits adipose inflammation to form functional fat, which contributes to its activity against insulin resistance. The insulin sensitization of Metrnl is blocked by PPARγ inhibitors or knockdown. However, Metrnl does not drive white adipose browning. Acute intravenous injection of recombinant Metrnl has no hypoglycemic effect, and 1-week intravenous administration of Metrnl is unable to rescue insulin resistance exacerbated by adipocyte Metrnl deficiency. Our results suggest adipocyte Metrnl controls insulin sensitivity at least via its local autocrine/paracrine action through the PPARγ pathway. Adipocyte Metrnl is an inherent insulin sensitizer and may become a therapeutic target for insulin resistance. PMID:26307585

  8. 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.

  9. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

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

  10. Insulin and glucose regulation.

    PubMed

    Ralston, Sarah L

    2002-08-01

    Abnormally high or low blood glucose and insulin concentrations after standardized glucose tolerance tests can reflect disorders such as pituitary dysfunction, polysaccharide storage myopathies, and other clinical disorders. Glucose and insulin responses, however, are modified by the diet to which the animal has adapted, time since it was last fed, and what it was fed. Body fat (obesity), fitness level, physiologic status, and stress also alter glucose and insulin metabolism. Therefore, it is important to consider these factors when evaluating glucose and insulin tests, especially if only one sample it taken. This article describes the factors affecting glucose and insulin metabolism in horses and how they might influence the interpretation of standardized tests of glucose tolerance.

  11. Use of Insulin Lispro Protamine Suspension in Pregnancy.

    PubMed

    Lapolla, Annunziata; Dalfrà, Maria Grazia; Romoli, Ester; Bonomo, Matteo; Moghetti, Paolo

    2015-10-01

    Maternal metabolism changes substantially during pregnancy, which poses numerous challenges to physicians managing pregnancy in women with diabetes. Insulin is the agent of choice for glycemic control in pregnant women with diabetes, and the insulin analogs are particularly interesting for use in pregnancy. These agents may reduce the risk of hypoglycemia and promote a more physiological glycemic profile than regular human insulin in pregnant women with type 1 (T1D), type 2 (T2D), or gestational (GDM) diabetes. However, there have been concerns regarding potential risk for crossing the placental barrier, mitogenic stimulation, teratogenicity, and embryotoxicity. Insulin lispro protamine suspension (ILPS), an intermediate- to long-acting insulin, has a stable and predictable pharmacological profile, and appears to have a favorable time-action profile and produce desirable basal and postprandial glycemic control. As the binding of insulin lispro is unaffected by the protamine molecule, ILPS is likely to have the same mitogenic and immunogenic potential as insulin lispro. Insulin lispro produces similar outcomes to regular insulin in pregnant women with T1D, T2D, or GDM, does not cross the placental barrier, and is considered a useful treatment option for pregnant women with diabetes. Clinical data support the usefulness of ILPS for basal insulin coverage in non-pregnant patients with T1D or T2D, and suggest that the optimal regimen, in terms of balance between efficacy and hypoglycemic risk, is a once-daily injection, especially in patients with T2D. Available data concerning use of ILPS in pregnant women are currently derived from retrospective analyses that involved, in total, >1200 pregnant women. These analyses suggest that ILPS is at least as safe and effective as neutral protamine Hagedorn insulin. Thus, available experimental and clinical data suggest that ILPS once daily is a safe and effective option for the management of diabetes in pregnant women. PMID

  12. 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.

  13. 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.

  14. Insulin and insulin-like growth factor I (IGF-I) stimulate GLUT4 glucose transporter translocation in Xenopus oocytes.

    PubMed Central

    Mora, S; Kaliman, P; Chillarón, J; Testar, X; Palacín, M; Zorzano, A

    1995-01-01

    1. The heterologous expression of glucose transporters GLUT4 and GLUT1 in Xenopus oocytes has been shown to cause a differential targeting of these glucose-carrier isoforms to cellular membranes and a distinct induction of glucose transport activity. In this study we have evaluated the effect of insulin and insulin-like growth factor I (IGF-I) on glucose uptake and glucose transporter distribution in Xenopus oocytes expressing mammalian GLUT4 and GLUT1 glucose carriers. 2. Insulin and IGF-I stimulated 2-deoxyglucose uptake in GLUT4-expressing oocytes, but not in GLUT1-expressing oocytes or in water-injected oocytes. The stimulatory effect of insulin and IGF-I on 2-deoxyglucose uptake in GLUT4-expressing oocytes occurred via activation of the IGF-I receptor. 3. Subcellular-fractionation studies indicated that insulin and IGF-I stimulated translocation of GLUT4 to the cell surface of the oocyte. 4. Incubation of intact oocytes with insulin stimulated phosphatidylinositol 3-kinase activity, an effect that was blocked by the additional presence of wortmannin. Furthermore, wortmannin totally abolished the insulin-induced stimulation of 2-deoxyglucose uptake in GLUT4-expressing oocytes. 5. In this study, both the insulin-induced GLUT4 carrier translocation and GLUT4-dependent insulin-stimulated glucose transport have been reconstituted in the Xenopus oocyte. These observations, together with the fact that wortmannin, as found in adipocytes, inhibits insulin-stimulated glucose transport in oocytes, suggest that the heterologous expression of GLUT4 in oocytes is a useful experimental model by which to study the cell biology of insulin-induced GLUT4 translocation. Images Figure 2 Figure 3 PMID:7575481

  15. The chronic intracerebroventricular infusion of interleukin-1 beta alters the activity of the hypothalamic-pituitary-gonadal axis of cycling rats. I. Effect on LHRH and gonadotropin biosynthesis and secretion.

    PubMed

    Rivest, S; Lee, S; Attardi, B; Rivier, C

    1993-12-01

    We have previously reported that the acute injection of interleukin-1 beta (IL-1 beta) into the brain ventricles of intact female rats promptly decreases LHRH release and inhibits gene expression of this peptide in the medial preoptic area (MPOA). The present studies were therefore designed to determine whether continuous exposure to the cytokine would disrupt the estrous cycle. IL-1 beta was injected intracerebroventricularly for 4-6 days at a rate of 4 ng/h. Daily vaginal smears were obtained to follow the cycle; pituitary LH and FSH secretion were measured at regular intervals. Steady state levels of LH and FSH messenger RNA (mRNA) in the pituitary, and LHRH gene expression in the MPOA, were measured at the end of the treatment. Infusion of IL-1 beta caused a total disruption of the estrous cycle, characterized by persistent smears indicative of the diestrus stage. When compared to animals treated with the vehicle, rats infused with IL-1 beta showed a significant decrease in circulating LH concentrations, which was accompanied by lowered mRNA levels in the pituitary. This statistical difference (P < 0.01) persisted even when treated rats were compared to control in a similar stage of the cycle (i.e. diestrus). Plasma FSH levels remained low at all times after IL-1 beta infusion but showed the expected cyclic changes in control animals. At the end of treatment, LHRH gene expression was also markedly suppressed in LHRH neurons distributed between the rostral preoptic area/organum vasculosum of the lamina terminalis and the MPOA of these animals. These results indicate that prolonged infusion of IL-1 beta into brain ventricles disrupts the estrous cycle, an event accompanied by decreased biosynthesis/release of LHRH and gonadotropins. We report in a related study that IL-1-treated rats also show increased plasma progesterone levels. However, it is improbable that this change was responsible for the interruption of the cycle described here; indeed we have previously

  16. 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.

  17. The Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Compared With Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily

    PubMed Central

    Meneghini, Luigi; Atkin, Stephen L.; Gough, Stephen C.L.; Raz, Itamar; Blonde, Lawrence; Shestakova, Marina; Bain, Stephen; Johansen, Thue; Begtrup, Kamilla; Birkeland, Kåre I.

    2013-01-01

    OBJECTIVE The requirement to inject current basal insulin analogs at a fixed time each day may complicate adherence and compromise glycemic control. This trial evaluated the efficacy and safety of varying the daily injection time of insulin degludec (IDeg), an ultra-long-acting basal insulin. RESEARCH DESIGN AND METHODS This 26-week, open-label, treat-to-target trial enrolled adults (≥18 years) with type 2 diabetes who were either insulin naïve and receiving oral antidiabetic drugs (OADs) (HbA1c = 7–11%) or previously on basal insulin ± OAD(s) (HbA1c = 7–10%). Participants were randomized to 1) once-daily (OD) IDeg in a prespecified dosing schedule, creating 8–40-h intervals between injections (IDeg OD Flex; n = 229); 2) once-daily IDeg at the main evening meal (IDeg OD; n = 228); or 3) once-daily insulin glargine at the same time each day (IGlar OD; n = 230). The primary outcome was noninferiority of IDeg OD Flex to IGlar OD in HbA1c reduction after 26 weeks. RESULTS After 26 weeks, IDeg OD Flex, IDeg OD, and IGlar OD improved HbA1c by 1.28, 1.07, and 1.26% points, respectively (estimated treatment difference [IDeg OD Flex − IGlar OD]: 0.04% points [–0.12 to 0.20], confirming noninferiority). No statistically significant differences in overall or nocturnal hypoglycemia were found between IDeg OD Flex and IGlar OD. Comparable glycemic control and rates of hypoglycemia were seen with IDeg OD Flex and IDeg OD. Adverse event profiles were similar across groups. CONCLUSIONS The use of extreme dosing intervals of 8–40 h demonstrates that the daily injection time of IDeg can be varied without compromising glycemic control or safety. PMID:23340894

  18. Impact of the Type of Continuous Insulin Administration on Metabolism in a Diabetic Rat Model.

    PubMed

    Schaschkow, A; Mura, C; Dal, S; Langlois, A; Seyfritz, E; Sookhareea, C; Bietiger, W; Peronet, C; Jeandidier, N; Pinget, M; Sigrist, S; Maillard, E

    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

  19. 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

  20. 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

  1. [Insulin and physical exercise].

    PubMed

    Louis-Sylvestre, J

    1987-04-01

    Secretion of some pituitary hormones and sympatho-adrenal activity increase very early during exercise. Sympathetic activation is of major importance in cardiovascular adaptation, thermoregulation, etc. Furthermore among the hormonal consequences of such activation those related to insulin are capital. In animal and human subjects basal insulin level decrease during prolonged and progressive exercise. With habitual exercise, both basal and stimulated insulin levels are reduced. It seems that the reduced basal level could be due to alpha-adrenergic inhibition of the islets of Langerhans, while the reduced stimulated response could be the consequence of increased clearance. In trained subjects, in spite of reduced insulin secretion tolerance to glucose is normal due to increased sensitivity to insulin. Sensitivity to insulin is particularly enhanced at the muscular tissue level; it is accompanied by increased hexokinase and glycogen synthetase activity. As a consequence glucose uptake remains optimal at the muscular level. In the liver, both insulin sensitivity and glucokinase activity are reduced, so that glucose is spared and the muscular glycogen store can be restored. At the adipocyte level, metabolic adaptations are such that triglyceride turnover is greatly increased, favouring fuel supply and resaturation of stores.

  2. 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.

  3. Management of severely brittle diabetes by continuous subcutaneous and intramuscular insulin infusions: evidence for a defect in subcutaneous insulin absorption.

    PubMed Central

    Pickup, J C; Home, P D; Bilous, R W; Keen, H; Alberti, K G

    1981-01-01

    Severely brittle diabetes is defined as a rare subtype of insulin-dependent diabetes with wide, fast, unpredictable, and inexplicable swings in blood glucose concentration, often culminating in ketoacidosis or hypoglycaemic coma. To assess the role of inappropriate type, amount, or timing of insulin treatment and the route of administration as a cause of severe brittleness six patients with continuous subcutaneous insulin infusion, which provides a high degree of optimisation of dosage with exogenous insulin in stable diabetics. The glycaemic control achieved during continuous subcutaneous insulin infusion was compared with that during continuous intramuscular insulin infusion. Six patients with non-brittle diabetes were also treated by continuous subcutaneous insulin infusion. These patients achieved the expected improvement in glycaemic control (mean +/- SD plasma glucose concentration 5.1 +/- 2.3 mmol/l (92 +/- 41 mg/100 ml)), but not the patients with brittle diabetes remained uncontrolled with continuous subcutaneous infusion (13.6 +/- 5.8 mmol/1 (245 +/- 105 mg/100 ml) compared with 10.3 +/- 4.1 mmol/l (186 +/- 74 mg/100 ml) during treatment with optimised conventional subcutaneous injections). During continuous intramuscular infusion, however, glycaemic control in five of the patients with brittle diabetes was significantly improved (7.7 +/- 2.6 mmol/l (139 +/- 47 mg/100 ml). The remaining patient with brittle diabetes, previously safely controlled only with continuous intravenous insulin, did not respond to continuous intramuscular infusion. It is concluded that in five of the six patients with brittle diabetes studied here impaired or irregular absorption of insulin from the subcutaneous site played a more important part in their hyperlability than inappropriate injection strategies. This absorption defect was presumably bypassed by the intramuscular route. PMID:6780019

  4. 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.

  5. Hydromorphone Injection

    MedlinePlus

    ... the body, vomiting, diarrhea, or failure to gain weight.tell your doctor if you are breast-feeding.if you ... Hydromorphone injection may cause side effects. Tell your doctor if any of these ... vomiting constipation dry mouth lightheadedness dizziness drowsiness ...

  6. Eculizumab Injection

    MedlinePlus

    ... which too many red blood cells are broken down in the body, so there are not enough healthy cells to bring oxygen to all parts of the body). Eculizumab injection is also used to treat atypical hemolytic uremic syndrome (aHUS; an inherited condition in which small blood ...

  7. Fluconazole Injection

    MedlinePlus

    ... injection is used to treat fungal infections, including yeast infections of the mouth, throat, esophagus (tube leading from the mouth to the stomach), abdomen (area between the chest and waist), lungs, blood, and ... to prevent yeast infections in patients who are likely to become infected ...

  8. Tositumomab Injection

    MedlinePlus

    ... has not improved or that had improved after treatment with other medications, but later returned. Tositumomab injection is in a class of medications called monoclonal antibodies with radioisotopes. It works by attaching to cancer cells and releasing radiation to damage the cancer ...

  9. Lanreotide Injection

    MedlinePlus

    Lanreotide injection is used to treat people with acromegaly (condition in which the body produces too much growth hormone, causing enlargement of the hands, feet, and facial features; joint pain; and other symptoms) who have not successfully, or cannot be treated ...

  10. Eribulin Injection

    MedlinePlus

    ... tests to check your body's response to eribulin injection.It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring ...

  11. Pegaptanib Injection

    MedlinePlus

    ... to 7 days after you receive each pegaptanib injection.It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring ...

  12. Insulin and the law.

    PubMed

    Marks, Vincent

    2015-11-01

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

  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. Insulin inhalation: NN 1998.

    PubMed

    2004-01-01

    Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal

  15. Functional Evaluation of the Reusable JuniorSTAR® Half-Unit Insulin Pen

    PubMed Central

    Klonoff, David; Nayberg, Irina; Rabbone, Ivana; Domenger, Catherine; Stauder, Udo; Oualali, Hamid; Danne, Thomas

    2015-01-01

    Background: The functional performance of the JuniorSTAR® (Sanofi, Paris, France) half-unit insulin pen was evaluated through a series of specific objective tests to assess the dose accuracy, pen weight, injection force, and dialing torque. Method: Pens (n = 60) were tested under standard atmospheric conditions with 3 different types of insulins manufactured by Sanofi (insulin glargine, insulin glulisine, and biphasic insulin isophane). The dose accuracy was tested according to the ISO 11608-1:2012 standards. Injection doses of 0.010, 0.155, and 0.300 ml were evaluated. For mean weight evaluation, the pens without the cartridge were weighed on precision balances. The injection force was measured using a texture analyzer and the dialing torque was measured using a torque meter. Results: JuniorSTAR met the ISO 11608-1:2012 criteria for dose accuracy as all the delivered doses were within the predefined limits for all types of insulin tested. The mean weight of the JuniorSTAR pen was 33.4 g (SD = 0.075). The mean injection force was 6.0 N (SD = 0.8), 4.3 N (SD = 0.4), and 5.1 N (SD = 0.6) for insulin glargine, insulin glulisine, and biphasic insulin isophane, respectively. The mean dialing torque was 5.09 Ncm (SD = 0.29) and 5.88 Ncm (SD = 0.53) for setting and correcting a dose, respectively. Conclusions: Together with results from a previously reported usability survey, these results show that the JuniorSTAR reusable, half-unit pen is a lightweight and accurate device for insulin delivery with a dialing torque and injection force suitable for young people with type 1 diabetes. PMID:25633967

  16. 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.

  17. All about Insulin Resistance

    MedlinePlus

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

  18. 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.

  19. Intracerebroventricular losartan infusion modulates angiotensin II type 1 receptor expression in the subfornical organ and drinking behaviour in bile-duct-ligated rats.

    PubMed

    Walch, Joseph D; Carreño, Flávia Regina; Cunningham, J Thomas

    2013-04-01

    Bile duct ligation (BDL) causes congestive liver failure that initiates haemodynamic changes, including peripheral vasodilatation and generalized oedema. Peripheral vasodilatation is hypothesized to activate compensatory mechanisms, including increased drinking behaviour and neurohumoral activation. This study tested the hypothesis that changes in the expression of angiotensin II type 1 receptor (AT(1)R) mRNA and protein in the lamina terminalis are associated with BDL-induced hyposmolality in the rat. All rats received either BDL or sham-ligation surgery. The rats were housed in metabolic chambers for measurement of fluid and food intake and urine output. Expression of AT(1)R in the lamina terminalis was assessed by Western blot and quantitative real-time PCR (RT-qPCR). Average baseline water intake increased significantly in BDL rats compared with sham-operated rats, and upregulation of AT(1)R protein and AT(1a)R mRNA were observed in the subfornical organ of BDL rats. Separate groups of BDL and sham-ligated rats were instrumented with minipumps filled with either losartan (2.0 μg μl(-1)) or 0.9% saline for chronic intracerebroventricular or chronic subcutaneous infusion. Chronic intracerebroventricular losartan infusion attenuated the increased drinking behaviour and prevented the increased abundance of AT(1)R protein in the subfornical organ in BDL rats. Chronic subcutaneous infusion did not affect water intake or AT(1)R abundance in the subfornical organ. The data presented here indicate a possible role of increased central AT(1)R expression in the regulation of drinking behaviour during congestive cirrhosis.

  20. Blockade of the Renin-Angiotensin system improves insulin receptor signaling and insulin-stimulated skeletal muscle glucose transport in burn injury.

    PubMed

    Kasper, Sherry O; Phillips, Erin E; Castle, Scott M; Daley, Brian J; Enderson, Blaine L; Karlstad, Michael D

    2011-01-01

    Burn injury is associated with a decline in glucose utilization and insulin sensitivity due to alterations in postreceptor insulin signaling pathways. We have reported that blockade of the renin-angiotensin system with losartan, an angiotensin II type 1 (AT1) receptor blocker, improves whole body insulin sensitivity and glucose metabolism after burn injury. This study examines whether losartan improves insulin signaling pathways and insulin-stimulated glucose transport in skeletal muscle in burn-injured rats. Rats were injured by a 30% full-skin-thickness scalding burn and treated with losartan or placebo for 3 days after burn. Insulin signaling pathways were investigated in rectus abdominus muscle taken before and 90 s after intraportal insulin injection (10 U·kg). Insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase and plasma membrane-associated GLUT4 transporter were substantially increased with losartan treatment in burn-injured animals (59% above sham). Serine phosphorylated AKT/PKB was decreased with burn injury, and this decrease was attenuated with losartan treatment. In a separate group of rats, the effect of insulin on 2-deoxyglucose transport was significantly impaired in burned as compared with sham soleus muscles, in vitro; however, treatment of burned rats with losartan completely abolished the reduction of insulin-stimulated 2-deoxyglucose transport. These findings demonstrate a cross talk between the AT1 and insulin receptor that negatively modulates insulin receptor signaling and suggest a potential role of renin-angiotensin system blockade as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle and improving whole-body glucose homeostasis in burn injury.

  1. Insulin signaling and addiction

    PubMed Central

    Daws, Lynette C.; Avison, Malcolm J.; Robertson, Sabrina D.; Niswender, Kevin D.; Galli, Aurelio; Saunders, Christine

    2012-01-01

    Across species, the brain evolved to respond to natural rewards such as food and sex. These physiological responses are important for survival, reproduction and evolutionary processes. It is no surprise, therefore, that many of the neural circuits and signaling pathways supporting reward processes are conserved from Caenorhabditis elegans to Drosophilae, to rats, monkeys and humans. The central role of dopamine (DA) in encoding reward and in attaching salience to external environmental cues is well recognized. Less widely recognized is the role of reporters of the “internal environment”, particularly insulin, in the modulation of reward. Insulin has traditionally been considered an important signaling molecule in regulating energy homeostasis and feeding behavior rather than a major component of neural reward circuits. However, research over recent decades has revealed that DA and insulin systems do not operate in isolation from each other, but instead, work together to orchestrate both the motivation to engage in consummatory behavior and to calibrate the associated level of reward. Insulin signaling has been found to regulate DA neurotransmission and to affect the ability of drugs that target the DA system to exert their neurochemical and behavioral effects. Given that many abused drugs target the DA system, the elucidation of how dopaminergic, as well as other brain reward systems, are regulated by insulin will create opportunities to develop therapies for drug and potentially food addiction. Moreover, a more complete understanding of the relationship between DA neurotransmission and insulin may help to uncover etiological bases for “food addiction” and the growing epidemic of obesity. This review focuses on the role of insulin signaling in regulating DA homeostasis and DA signaling, and the potential impact of impaired insulin signaling in obesity and psychostimulant abuse. PMID:21420985

  2. Moving toward the ideal insulin for insulin pumps.

    PubMed

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

    2016-01-01

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

  3. [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.

  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. PMID:27141654

  5. Memory modulation by post-training glucose or insulin remains evident at long retention intervals.

    PubMed

    Kopf, S R; Baratti, C M

    1996-03-01

    Immediate posttraining intraperitoneal injection of alpha-D[+]-glucose (30 mg/kg) facilitated, whereas a nonconvulsive dose of insulin (8 IU/kg) impaired, 24-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. When mice were trained and received immediate post-training glucose or insulin injections and were tested for retention either 1 week or 1 month later, at each retention interval performance was comparable to that found with a 24-h retention interval. Thus, memory modulation by post-training administration of either glucose or insulin remain evident at long retention intervals. PMID:8833107

  6. Memory modulation by post-training glucose or insulin remains evident at long retention intervals.

    PubMed

    Kopf, S R; Baratti, C M

    1996-03-01

    Immediate posttraining intraperitoneal injection of alpha-D[+]-glucose (30 mg/kg) facilitated, whereas a nonconvulsive dose of insulin (8 IU/kg) impaired, 24-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. When mice were trained and received immediate post-training glucose or insulin injections and were tested for retention either 1 week or 1 month later, at each retention interval performance was comparable to that found with a 24-h retention interval. Thus, memory modulation by post-training administration of either glucose or insulin remain evident at long retention intervals.

  7. 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. PMID:20515315

  8. Use of cross-reactivity immunoassay to orient insulin replacement in diabetic patients with high levels of insulin antibodies.

    PubMed

    Cardoso Landaburu, Alejandro; Pomares, María; Avalos, Alfredo; Lapertosa, Silvia; Frechtel, Gustavo; Poskus, Edgardo

    2016-01-01

    The prevalence and high levels of anti-insulin antibodies (IA) have frequently been associated with brittle diabetes, lipodystrophy in the areas where the insulin is injected and/or poor metabolic control. When this happens the usual criterion adopted is the empirical change of insulin type and/or formulation intending to diminish the IA level and then to decrease the undesirable side-effects. Here, we present a rational two step radiometric method consisting in: A) a first-line radioligand binding assay (RBA) to assess IA in sera of these patients and detecting those with high levels. B) applying a displacement assay (RIA) to determine the in vitro cross-reactivity parameters (affinity constants and selectivity ratios) that quantify the relative degree of interaction between antibodies and alternative insulin analogs. From these results we conclude that conventional criteria for selection of insulin analogs, in terms of pharmacokinetic and pharmacodinamic parameters, should be complemented with an appropriate test to assess affinity parameters when high IA title is demonstrated. •This manuscript introduces a rational method to determine the appropriated insulin replacement when high insulin antibodies levels are present.•This protocol provides instructions and details in mathematical tools and laboratory processes for the analysis of serum samples.•This method proved to be successful in a single case and requires confirmation using a large group of patients. PMID:27617231

  9. 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

  10. Chronic activation of central AMPK attenuates glucose-stimulated insulin secretion and exacerbates hepatic insulin resistance in diabetic rats.

    PubMed

    Park, Sunmin; Kim, Da Sol; Kang, Suna; Shin, Bae Keun

    2014-09-01

    We investigated the effects of chronic AMP-activated kinase (AMPK) activation in the hypothalamus on energy and glucose metabolism in 90% pancreatectomized diabetic rats. Diabetic rats fed a high fat diet were divided into 3 groups and intracerebroventricular (ICV) administered with one of the following: 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR, AMPK activator; 80 μg/day), AICAR+compound C (AMPK inhibitor; 6.2 μg/day), or an artificial cerebrospinal fluid (control) by means of osmotic pumps for 4 weeks. In the hypothalamus, central AICAR activated the phosphorylation of AMPK whereas adding compound C suppressed the activation. AICAR increased body weight and epididymal and retroperitoneal fat mass by increasing energy intake for the first 2 weeks and decreasing energy expenditure, whereas compound C reversed the AICAR effect on energy metabolism. Indirect calorimetry revealed that ICV-AICAR decreased carbohydrate oxidation, but not fat oxidation, compared to the control. During euglycemic hyperinsulinemic clamp, central AICAR increased hepatic glucose output at hyperinsulinemic states. ICV-AICAR increased expressions of hepatic genes involved in fatty acid synthesis and decreased expression of hepatic genes related to thermogenesis whereas compound C nullified the AICAR effect. Insulin secretion in the first and second phases decreased in AICAR-treated rats at hyperglycemic clamp, but compound C nullified the decrease. However, central AICAR did not alter β-cell mass via its proliferation or apoptosis. In conclusion, chronic hypothalamic AMPK activation impaired energy metabolism and glucose homeostasis by increasing food intake, increasing hepatic glucose output and decreasing insulin secretion in diabetic rats. The impairment of energy and glucose homeostasis by AMPK activation was nullified by an AMPK inhibitor.

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

    PubMed

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

    1998-11-01

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

  12. Insulin-producing cells.

    PubMed

    Schroeder, Insa S; Kania, Gabriela; Blyszczuk, Przemyslaw; Wobus, Anna M

    2006-01-01

    Embryonic stem (ES) cells offer great potential for cell replacement and tissue engineering therapies because of their almost unlimited proliferation capacity and the potential to differentiate into cellular derivatives of all three primary germ layers. This chapter describes a strategy for the in vitro differentiation of mouse ES cells into insulin-producing cells. The three-step protocol does not select for nestin-expressing cells as performed in previous differentiation systems. It includes (1) the spontaneous differentiation of ES cells via embryoid bodies and (2) the formation of progenitor cells of all three primary germ layers (multilineage progenitors) followed by (3) directed differentiation into the pancreatic lineage. The application of growth and extracellular matrix factors, including laminin, nicotinamide, and insulin, leads to the development of committed pancreatic progenitors, which subsequently differentiate into islet-like clusters that release insulin in response to glucose. During differentiation, transcript levels of pancreas-specific transcription factors (i.e., Pdx1, Pax4) and of genes specific for early and mature beta cells, including insulin, islet amyloid pancreatic peptide, somatostatin, and glucagon, are upregulated. C-peptide/insulin-positive islet-like clusters are formed, which release insulin in response to high glucose concentrations at terminal stages. The differentiated cells reveal functional properties with respect to voltage-activated Na+ and ATP-modulated K+ channels and normalize blood glucose levels in streptozotocin-treated diabetic mice. In conclusion, we demonstrate the efficient differentiation of murine ES cells into insulin-producing cells, which may help in the future to establish ES cell-based therapies in diabetes mellitus.

  13. 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. PMID:25227250

  14. Adenoviral vector-mediated insulin gene transfer in the mouse pancreas corrects streptozotocin-induced hyperglycemia.

    PubMed

    Shifrin, A L; Auricchio, A; Yu, Q C; Wilson, J; Raper, S E

    2001-10-01

    Therapy for type 1 diabetes consists of tight blood glucose (BG) control to minimize complications. Current treatment relies on multiple insulin injections or an insulin pump placement, beta-cell or whole pancreas transplantation. All approaches have significant limitations and have led to the realization that novel treatment strategies are needed. Pancreatic acinar cells have features that make them a good target for insulin gene transfer. They are not subject to autoimmune attack, a problem with pancreas or islets transplantation, they are avidly transduced by recombinant adenoviral vectors, and capable of exporting a variety of peptides into the portal circulation. Recombinant adenoviral vectors were engineered to express either wild-type or furin-modified human insulin cDNA (AdCMVhInsM). Immunodeficient mice were made diabetic with streptozotocin and injected intrapancreatically with the vectors. BG and blood insulin levels have normalized after administration of AdCMVhInsM. Immunohistochemistry and electron microscopy showed the presence of insulin in acinar cells throughout the pancreas and localization of insulin molecules to acinar cell vesicles. The data clearly establish a relationship between intrapancreatic vector administration, decreased BG and elevated blood insulin levels. The findings support the use of pancreatic acinar cells to express and secrete insulin into the blood stream. PMID:11593361

  15. Factors affecting the response to insulin in the normal subhuman pregnant primate

    PubMed Central

    Chez, Ronald A.; Mintz, Daniel H.; Horger, Edgar O.; Hutchinson, Donald L.

    1970-01-01

    The concentrations of plasma glucose, free fatty acids, insulin, growth hormone, and placental prolactin in subhuman primate fetal and maternal plasma were examined following intravascular administration of insulin and glucagon to the fetus and mother. The neonatal plasma responses to these same stimuli were also examined. Fetal plasma glucose concentrations were minimally altered by direct fetal insulin injections, whereas neonatal glucose levels declined with similar injections. In both instances, however, plasma free fatty acid levels declined following insulin. When the amount of insulin given the fetus was increased, fetal plasma glucose concentrations did decline. Combined intravascular insulin injections and infusions in the mother were associated with a disappearance of the initial maternal to fetal plasma glucose concentration gradient and a nearly parallel fall in both maternal and fetal plasma glucose levels. It was concluded that insulin was biologically active in the fetus. Obtunded fetal plasma glucose responses to direct fetal insulin administration may be a function of placental transfer of glucose from the maternal pool. Maternal plasma placental prolactin and fetal plasma growth hormone levels were unchanged in the presence of sustained maternal and fetal hypoglycemia. However, neonatal plasma growht hormone levels did increase in response to hypoglycemia. The observed bidirectional placental barrier to transfer of radioisotopically labeled growth hormone indicated that fetal plasma growth hormone was solely of fetal origin. These data suggested further that a change in the growth hormone-releasing mechanism may occur from fetal to neonatal life. Direct maternal intravascular glucagon administration led to augmentation in both maternal and fetal plasma insulin and glucose levels. Direct fetal glucagon injections enhanced both maternal and fetal plasma insulin levels. These simultaneous changes in both plasma pools were consistent with the

  16. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

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

  17. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

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

  18. 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)

  19. 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.

  20. Injectable contraception.

    PubMed

    Kaunitz, A M

    1989-06-01

    The most effective, convenient, reversible method of birth control is considered to be long-acting progestogen injections. Used by over 90 countries, Depot medroxy-progesterone acetate (DMPA, Depo-Provera, Upjohn) has yet to be approved by the U.S. Food and Drug Administration. The reluctance of the FDA to approve DMPA and much of the controversy surrounding this method revolve around the results of testing done on animals who were given large doses of the progestogen over a long period of time and developed tumors. However, the large body of research and records on this method that have been compiled over the past 30 years is positive. The injectable method works like oral contraceptives, inhibiting ovulation. Changes in menstruation have been the chief complaint of women who use this method; however, the duration and frequency of spotting and bleeding diminish over time. Other side effects of DMPA and Norethindrone enanthate (NET EN, Noristerat, Schering) are discussed. Also discussed is the history of development and testing for the 2 methods and subdermal implants, specifically Norplant.

  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. A major role of insulin in promoting obesity-associated adipose tissue inflammation

    PubMed Central

    Pedersen, David J.; Guilherme, Adilson; Danai, Laura V.; Heyda, Lauren; Matevossian, Anouch; Cohen, Jessica; Nicoloro, Sarah M.; Straubhaar, Juerg; Noh, Hye Lim; Jung, DaeYoung; Kim, Jason K.; Czech, Michael P.

    2015-01-01

    Objective Adipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of its receptor on target tissues. Here we tested the novel hypothesis that insulin also impairs systemic insulin sensitivity by specifically enhancing adipose inflammation. Methods Circulating insulin levels were reduced by about 50% in diet-induced and genetically obese mice by treatments with diazoxide or streptozotocin, respectively. We then examined AT crown-like structures, macrophage markers and pro-inflammatory cytokine expression in AT. AT lipogenesis and systemic insulin sensitivity was also monitored. Conversely, insulin was infused into lean mice to determine its affects on the above parameters. Results Lowering circulating insulin levels in obese mice by streptozotocin treatment decreased macrophage content in AT, enhancing insulin stimulated Akt phosphorylation and de novo lipogenesis (DNL). Moreover, responsiveness of blood glucose levels to injected insulin was improved by streptozotocin and diazoxide treatments of obese mice without changes in body weight. Remarkably, even in lean mice, infusion of insulin under constant euglycemic conditions stimulated expression of cytokines in AT. Consistent with these findings, insulin treatment of 3T3-L1 adipocytes caused a 10-fold increase in CCL2 mRNA levels within 6 h, which was blocked by the ERK inhibitor PD98059. Conclusion Taken together, these results indicate that obesity-associated hyperinsulinemia unexpectedly drives AT inflammation in obese mice, which in turn contributes to factors that suppress insulin-stimulated adipocyte DNL and systemic insulin sensitivity. PMID:26137438

  3. 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

  4. Regulation of pancreatic somatostatin gene expression by insulin and glucagon.

    PubMed

    Ehrman, Melissa M; Melroe, Gregory T; Kittilson, Jeffrey D; Sheridan, Mark A

    2005-05-12

    Rainbow trout were used as a model system to study the effects of insulin and glucagon on the expression of preprosomatostatins (PPSS). We previously showed that the endocrine pancreas of trout contains three mRNAs that encode for distinct somatostatin-containing peptides: PPSS I, which contains somatostain-14 (SS-14) at its C-terminus, and two separate PPSS IIs, PPSS II' and PPSS II'', each containing [Tyr7, Gly10]-SS-14 at their C-terminus. Rainbow trout injected (100 ng/g body weight) with insulin displayed elevated expression of PPSS II' and PPSS II'' mRNAs. Glucagon-injected (100 ng/g body weight) animals displayed elevated pancreatic expression of all PPSS mRNAs compared to saline-injected control animals. Insulin directly stimulated the expression of pancreatic PPSS II' and PPSS II'' mRNAs in vitro in a dose-dependent manner in the presence of 4mM glucose. Glucagon, in the presence of 10mM glucose, directly stimulated the expression of all PPSS mRNAs in a dose-dependent manner in vitro. These results indicate that the pancreatic expression of PPSS mRNAs is differentially regulated by insulin and glucagon and that the regulatory pattern is dependent on glucose concentration. PMID:15866425

  5. Insulin tolerance in laminitic ponies.

    PubMed Central

    Coffman, J R; Colles, C M

    1983-01-01

    Sensitivity to insulin was assessed in ponies episodically affected with chronic laminitis by measurement of blood glucose and arterial blood pressure during insulin tolerance tests. In terms of blood glucose values, laminitic ponies were significantly less sensitive to insulin than controls. Conversely, a post-insulin decline in diastolic, systolic and mean blood pressure values was significantly greater in laminitic ponies than in controls. PMID:6357412

  6. Epidural Steroid Injections

    MedlinePlus

    ... Assessment Tools Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysial (Facet) Joint Injections Surgical Options Nonsurgical Treatments Alternative Medicine Epidural Steroid Injections General Information Why Get an Epidural Steroid ...

  7. Prevalence of morning hyperglycaemia: determinants of fasting blood glucose concentrations in insulin-treated diabetics.

    PubMed

    Francis, A J; Home, P D; Walford, S; Alberti, K G; Mann, N; Reeves, W G

    1985-03-01

    A rise in blood glucose concentration at the end of the night, and consequent morning hyperglycaemia, are well recognized events in some diabetic patients. In 94 patients on twice daily insulin injections we have examined the prevalence and extent of morning hyperglycaemia, and its relation to control, insulin therapy, and insulin antibody levels. Blood glucose reached the highest level of the day before or after breakfast in 83% of patients, and in 50% this value was 2 mmol/l greater than any other time of day. Patients with higher fasting concentrations did not have worse blood glucose control over the rest of the day. No correlation was found between fasting blood glucose concentrations and the evening dose of intermediate acting insulin or the level of insulin antibodies. No consistent change in fasting blood glucose concentrations occurred with changes in antibody levels in patients switched between pork and beef insulin. Morning hyperglycaemia was as common with both insulin species. Pre- and post-breakfast hyperglycaemia is common and significant in insulin-treated diabetic patients. It is not directly related to diabetic control at other times of the day, and is independent of insulin species and insulin antibody levels.

  8. [Estimation of different models of insulin therapy in noninsulin-dependent diabetes mellitus].

    PubMed

    Trznadel-Morawska, I; Małecki, M; Sieradzki, J

    1997-01-01

    The aim of the study was to find out which model of insulin therapy in patients with noninsulin-dependent diabetes mellitus with secondary inefficacy of sulphonylurea is most effective for glycemia normalization, inhibition of late complications, prevention of atherosclerosis and better quality of life. In 27 patients aged 40-70 years with a history of diabetes over 3 years, BMI < 30, treated with maximal doses of Euclamine we applied 4 therapeutic models: 1) intensive insulin therapy (M1), 2) two injections of three insulins (M2), 3) Euclamin 20 mg + intermediate insulin (M3), 4) Euclamine 20 mg + intermediate insulin (M4). The study lasted 3 months whereas education was carried out within the first two weeks. The following parameters were evaluated: beta cell reserve (glibenclamide test), peptide C level, HbA1C concentration, glycemia profile, lipids, creatinine level. Foci of infection were eradicated. It was found out that: 1) all models of insulin therapy, produced near normoglycemia, 2) the model of intensive insulin therapy does not generate hyperinsulinism in face of body weight loss and improved lipid profile, 3) the model of intensive insulin therapy shows long-term efficacy in the absence of effects when assessing fasting glycemia state (HbA1C, Schilchtkrull's index, lipid indices), 4) the model combining Euclamine with intermediate insulin is on intermediate step leading to another form of insulin therapy. PMID:9380804

  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. Tedium among patients with insulin-dependent diabetes mellitus.

    PubMed

    Lundman, B; Asplund, K; Norberg, A

    1988-01-01

    Tedium assessment and factor analysis of psychosocial variables were performed in 158 insulin-dependent diabetic patients. High tedium scores correlated significantly (P less than 0.05) with high education, lack of self-monitoring, many reported problems concerning insulin injections, diet, strict planning of the activities of everyday life and anxiety concerning complications. There was also a significant relationship between low tedium scores and reported positive effects of the diabetes. There was a higher proportion (ns) of high tedium scores among patients in poor or good metabolic control than in those with intermediate metabolic control. PMID:3372882

  11. 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.

  12. 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.

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

    PubMed Central

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

    2014-01-01

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

  14. Insulin-induced hypoglycemia activates the release of adrenocorticotropin predominantly via central and propranolol insensitive mechanisms.

    PubMed

    Jezová, D; Kvetnanský, R; Kovács, K; Oprsalová, Z; Vigas, M; Makara, G B

    1987-01-01

    The dynamic patterns of pituitary-adrenocortical and sympatho-adrenal hormone responses to insulin hypoglycemia as well as the relative importance of central vs. peripheral control of hypoglycemia-induced ACTH secretion were evaluated. In conscious rats bearing indwelling cannulae, the changes in hormone concentrations after insulin injection were dependent on the changes in blood glucose levels with respect to both time course and magnitude. ACTH, corticosterone, epinephrine, and norepinephrine levels were found to be maximal at 60 min after 2.5 IU kg-1 insulin injected ip, whereas earlier (20 min) but smaller increases were obtained in response to 0.5 IU kg-1 insulin injected iv. In rats 6-7 days after lesions of the medial basal hypothalamus (MBH), the rise of ACTH during insulin hypoglycemia was markedly inhibited and corticosterone levels were significantly reduced. Simultaneously, the hypoglycemia-induced increase in plasma epinephrine was unchanged and that in plasma norepinephrine was significantly enhanced in rats with the MBH destroyed. The beta-adrenoreceptor blocker propranolol did not inhibit ACTH and corticosterone responses to hypoglycemia in either sham-operated or MBH-lesioned animals. We conclude that the main factors triggering ACTH release during insulin-induced hypoglycemia are of central rather than peripheral origin. The high concentrations of circulating catecholamines occurring during insulin hypoglycemia are not responsible for pituitary-adrenocortical activation by direct, beta-adrenoreceptor mediated action at the pituitary level. PMID:3023036

  15. [Insulin therapy of diabetes].

    PubMed

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

    2016-04-01

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

  16. Insulin Resistance and Prediabetes

    MedlinePlus

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

  17. Insulin therapy and exercise.

    PubMed

    Kourtoglou, Georgios I

    2011-08-01

    Medical nutrition therapy and physical exercise are the cornerstones of the diabetes management. Patients with type 1 DM always need exogenous insulin administration, recently available in the form of insulin analogs. In type 2 DM, characterized by increased insulin resistance and progressive decline of the beta-cell function, various antidiabetic medications are used. Most of the subjects with type 2 DM will finally need insulin. The main site of insulin action is the skeletal muscle, while the liver is the main site of glucose storage in the form of glycogen. With the modern diabetes therapies it is possible to rapidly reach and maintain normoglycemia in both types of DM but with the cost of higher incidence of hypoglycemia, especially related to exercise. Regular physical exercise causes a lot of beneficial effects in healthy as well as diabetic subjects of all age groups. In type 1 DM physical exercise is a fundamental element for both physical and mental development. In type 2 DM it has a main role in diabetes control. The increased hepatic glucose production and the increased muscular glucose uptake during exercise are closely interrelated in all exercise intensities. In diabetes mellitus there is a disturbed energy substrate use during exercise leading to either hypo- or hyperglycemia. The influence of low or moderate intensity aerobic exercise on diabetes control has been well studied. The inappropriately high insulinemia combined with the low glucose levels can lead to severe hypoglycemia if proper measures are not taken. Prolonged exercise can also predispose to decreased glucose counter regulation. It is better for the type 1 diabetic subject to postpone the exercise session in very high (>300 mg/dl) or very low (<70 mg/dl) BG levels. Every insulin treated subject is recommended to be checked for any existing diabetic complication before the start of every exercise program. Glucose measurement with glucose meters or sometimes with Continuous Glucose

  18. Prevalence of lipohypertrophy in insulin-treated diabetic patients and predisposing factors.

    PubMed

    Hauner, H; Stockamp, B; Haastert, B

    1996-01-01

    In a cross-sectional study the frequency of insulin-induced lipohypertrophy at injection sites was assessed in 223 type 1 and 56 type 2 diabetic patients. 64 (28.7%) of the subjects with type 1 diabetes, but only 2 (3.6%) of those with type 2 diabetes presented clinical evidence of lipohypertrophy. In every second affected type 1 diabetic patient lipohypertrophy developed within 2 years after starting insulin therapy. The occurrence of lipohypertrophy was independent of the insulin source and mode of therapy. In a multivariate logistic regression analysis young age, low body mass index, abdominal injection site and, particularly, missing rotation of injection site were significant independent risk factors for the presence of insulin-induced lipohypertrophy. Avoidance of such areas led to a partial or full remission of tissue swellings in 6 of 11 cases under observation for one year. In conclusion, lipohypertrophy is still a frequent complication of insulin therapy. To prevent such local skin reactions insulin-treated patients should be more intensively trained to regularly change injection sites.

  19. Arousal of a specific and persistent sodium appetite in the rat with continuous intracerebroventricular infusion of angiotensin II.

    PubMed

    Bryant, R W; Epstein, A N; Fitzsimons, J T; Fluharty, S J

    1980-04-01

    1. Prolonged exposure of the brain of the normal Na-replete rat to angiotensin II produced a marked and persistent Na appetite. In a first series of experiments, short-term, repeated systemic injections of isoprenaline or renin (both of which raise circulating angiotensin levels), and repeated intracranial injections of angiotensin II evoked increased ingestion of 2 . 7% NaCl. In the second series of experiments, continuous infusions of angiotensin II directly into the brain evoked extremely large intakes of 3% NaCl. 2. In addition to large intakes of hypertonic NaCl some rats drank daily volumes of water that exceeded their body weight. 3. Not only did the animals drink large volumes of 3% NaCl some rats drank daily volumes of water that exceeded their body weight. 3. Not only did the animals drink large volumes of 3% NaCl during continuous angiotensin II infusion, but after termination of the infusion they continued to ingest NaCl at a rate comparable to that of the adrenalectomized rat. In most of the animals the persistent NaCl intake diminished over several days, but other animals continued to drink NaCl for as long as their intake was measured (up to 7 months). 4. The response to continuous infusion of angiotensin II was dose-dependent. Both water and 3% NaCl intake increased over a dose range of 6 ng h-1 to 6000 ng h-1. The persistence of the sodium appetitite was also dose-dependent across the same range of doses. 5. Angiotensin-induced salt appetite is specific for Na. Animals did not drink 0 . 5 M-NH4Cl and only occasionally drank minimal amounts of 0 . 5 M-KCl during continuous infusion. 6. The large water turnover was not responsible for the Na appetite. Rats given access to 3% NaCl only during infusion of angiotensin copiously. Animals that were not infused but were given saccharine-flavoured water in order to increase their water intakes did not drink 3% NaCl offered at the same time even though fluid intake was high. Rats that did not receive

  20. Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy

    PubMed Central

    Armbruster, Nicole; Lattanzi, Annalisa; Jeavons, Matthieu; Van Wittenberghe, Laetitia; Gjata, Bernard; Marais, Thibaut; Martin, Samia; Vignaud, Alban; Voit, Thomas; Mavilio, Fulvio; Barkats, Martine; Buj-Bello, Ana

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery. PMID:27652289

  1. Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy

    PubMed Central

    Armbruster, Nicole; Lattanzi, Annalisa; Jeavons, Matthieu; Van Wittenberghe, Laetitia; Gjata, Bernard; Marais, Thibaut; Martin, Samia; Vignaud, Alban; Voit, Thomas; Mavilio, Fulvio; Barkats, Martine; Buj-Bello, Ana

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery.

  2. Effect of hydrophobic scaffold on the cellular uptake and gene transfection activities of DNA-encapsulating liposomal nanoparticles via intracerebroventricular administration.

    PubMed

    Akita, Hidetaka; Nakatani, Taichi; Kuroki, Kimiko; Maenaka, Katsumi; Tange, Kota; Nakai, Yuta; Harashima, Hideyoshi

    2015-07-25

    Efficient DNA carriers are needed as a gene medication for curing brain disorders. In the present study, the function of a neutral lipid envelope-type nanoparticle (LNP) encapsulating pDNA was evaluated after intracerebroventricular administration. The lipid envelope was composed of a series of SS-cleavable and pH-activated lipid like materials (ssPalm) including myristic acid, vitamin A and vitamin E in the hydrophobic scaffold (LNPssPalmM, LNPssPalmA, LNPssPalmE, respectively). The LNPssPalmA and LNPssPalmE were extensively distributed in the corpus callosum, and then gene expression occurred mainly astrocytes in this region, while not in LNPssPalmM. The recombinant human ApoE3-dependent enhancement of the uptake into an astrocyte-derived cell line (KT-5) was observed in LNPssPalmA and LNPssPalmE. Thus, ApoE in the brain plays a key role in the cellular uptake of these particles by astrocytes, and this uptake is dependent on the structure of the hydrophobic scaffold.

  3. Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy.

    PubMed

    Armbruster, Nicole; Lattanzi, Annalisa; Jeavons, Matthieu; Van Wittenberghe, Laetitia; Gjata, Bernard; Marais, Thibaut; Martin, Samia; Vignaud, Alban; Voit, Thomas; Mavilio, Fulvio; Barkats, Martine; Buj-Bello, Ana

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery. PMID:27652289

  4. Nilotinib exacerbates diabetes mellitus by decreasing secretion of endogenous insulin.

    PubMed

    Ito, Yoshikiyo; Miyamoto, Toshihiro; Chong, Yong; Maki, Toshinobu; Akashi, Koichi; Kamimura, Tomohiko

    2013-01-01

    We report a 74-year-old female with chronic myelogenous leukemia (CML) in accelerated phase with pre-existing severe type 2 diabetes (T2D) and hemorrhagic gastric ulcers who was successfully treated with nilotinib. We first considered second-generation tyrosine kinase inhibitors for the treatment of this patient, as they elicit a superior response compared with imatinib. We next selected nilotinib, rather than dasatinib, since the increased risk of bleeding associated with dasatinib represented a greater risk of fatality than aggravation of T2D with nilotinib. After improvement of hemorrhagic gastric ulcers and T2D with exogenous insulin therapy, we began nilotinib administration; insulin dose was increased to maintain her glucose levels whereas urine C-peptide level decreased. Conversely, when nilotinib was discontinued due to liver dysfunction, the dosage of injected insulin was decreased and urine C-peptide levels increased. After re-starting nilotinib, the required dose of insulin gradually increased again, and urine C-peptide level decreased, indicating that nilotinib may have impaired secretion of endogenous insulin. The patient obtained a complete cytogenetic response after 3 months of nilotinib treatment. Her T2D has since been well controlled by insulin therapy. To our knowledge, this is the first report that nilotinib treatment for patients with severe T2D may induce a reversible decrease in endogenous insulin secretion, although the precise underlying mechanisms remain unknown. We highly recommend sufficient screening and early intervention with exogenous insulin therapy for diabetic CML patients who receive nilotinib.

  5. Evidence against extrapancreatic insulin synthesis.

    PubMed Central

    Eng, J; Yalow, R S

    1981-01-01

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

  6. Insulin degludec for diabetes mellitus.

    PubMed

    2013-07-01

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

  7. Insulin Causes Hyperthermia by Direct Inhibition of Warm-Sensitive Neurons

    PubMed Central

    Sanchez-Alavez, Manuel; Tabarean, Iustin V.; Osborn, Olivia; Mitsukawa, Kayo; Schaefer, Jean; Dubins, Jeffrey; Holmberg, Kristina H.; Klein, Izabella; Klaus, Joe; Gomez, Luis F.; Kolb, Hartmuth; Secrest, James; Jochems, Jeanine; Myashiro, Kevin; Buckley, Peter; Hadcock, John R.; Eberwine, James; Conti, Bruno; Bartfai, Tamas

    2010-01-01

    OBJECTIVE Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT). RESEARCH DESIGN AND METHODS The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[18F]fluoro-2-deoxyglucose uptake into brown adipose tissue (BAT) was measured in rats after insulin treatment by positron emission tomography combined with X-ray computed tomography imaging. Insulin receptor–positive neurons were identified by retrograde tracing from the raphe pallidus. Insulin was locally applied on hypothalamic slices to determine the direct effects of insulin on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. RESULTS Injection of insulin into the preoptic area of the hypothalamus induced a specific and dose-dependent elevation of CBT mediated by stimulation of BAT thermogenesis as shown by imaging and respiratory ratio measurements. Retrograde tracing indicates that insulin receptor–expressing warm-sensitive neurons activate BAT through projection via the raphe pallidus. Insulin applied on hypothalamic slices acted directly on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. The hyperthermic effects of insulin were blocked by pretreatment with antibodies to insulin or with a phosphatidylinositol 3–kinase inhibitor. CONCLUSIONS Our findings demonstrate that insulin can directly modulate hypothalamic neurons that regulate thermogenesis and CBT and indicate that insulin plays an important role in coupling metabolism and thermoregulation at the level of anterior hypothalamus. PMID:19846801

  8. Antihyperglycemic effect of insulin from self-dissolving micropiles in dogs.

    PubMed

    Ito, Yukako; Ohashi, Yoshinori; Saeki, Atsushi; Sugioka, Nobuyuki; Takada, Kanji

    2008-03-01

    As a percutaneous delivery device, self-dissolving micropiles (SDMPs) composed of chondroitin sulfate and insulin were prepared under room temperature from highly concentrated solution, glue. The mean weight of SDMP was 1.03+/-0.04 mg. One insulin SDMP was percutaneously administered to the shaved abdominal skin of four beagle dogs at insulin dose level of 1.0 and 2.0 IU/dog. After administration, blood samples were collected for 6 h and plasma glucose levels were measured. The time when minimum plasma glucose level appeared, T(min), was 1.38+/-0.2 h for 1.0 IU study and 1.38+/-0.1 h for 2.0 IU study and clear dose-dependent hypoglycemic effect of insulin was observed in the dose range. By comparing the area above the plasma glucose level vs. time curve (AAC) between insulin SDMP and subcutaneous (s.c.) injection solution, the relative pharmacological availabilities were 99% (1.0 IU) and 90% (2.0 IU), respectively. To ascertain the usefulness of insulin SDMP, oral glucose tolerance test (OGTT) was performed. When dogs were treated with insulin SDMPs, 2.0 IU, followed by an OGTT 30 min, glycemia did not appear for 5 h. On the other hand, when OGTT was performed at 1 h after insulin SDMP administration, hypoglycemia appeared as in the case of s.c. injection of insulin solution, 2.0 IU. Insulin SDMP improved the oral glucose challenge for 3 h, with a maximum effect at 30 min before the administration of glucose. Those results suggest the usefulness of a SDMP for the percutaneous delivery of peptide/protein drugs like insulin.

  9. Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

    PubMed Central

    Boini, Krishna M.; Graf, Dirk; Hennige, Anita M.; Koka, Saisudha; Kempe, Daniela S.; Wang, Kan; Ackermann, Teresa F.; Föller, Michael; Vallon, Volker; Pfeifer, Karl; Schleicher, Erwin; Ullrich, Susanne; Häring, Hans-Ulrich; Häussinger, Dieter; Lang, Florian

    2009-01-01

    The pore-forming K+-channel α-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K+ uptake and glucose metabolism. Insulin (100 nM)-induced K+ uptake was determined in isolated perfused livers from KCNQ1-deficient mice (kcnq1−/−) and their wild-type littermates (kcnq1+/+). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled 3H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular K+ uptake was significantly more sustained in isolated perfused livers from kcnq1−/− mice than from kcnq1+/+mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in kcnq1−/− than in kcnq1+/+ mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in kcnq1−/− than in kcnq1+/+mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in kcnq1−/− than in kcnq1+/+mice. Uptake of 3H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in kcnq1−/− than in kcnq1+/+mice. In conclusion, KCNQ1 counteracts the stimulation of cellular K+ uptake by insulin and thereby influences K+-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism. PMID:19369585

  10. The Effect of Gastrin on Basal- and Glucose-Stimulated Insulin Secretion in Man

    PubMed Central

    Rehfeld, Jens F.; Stadil, Flemming

    1973-01-01

    The effect of gastrin on basal- and glucose-stimulated insulin secretion was studied in 32 normal, young subjects. The concentration of gastrin and insulin in serum was measured radioimmunochemically. Maximal physiologic limit for the concentration of gastrin in serum was of the order of 160 pmol per liter as observed during a protein-rich meal. Oral ingestion of 50 g glucose produced a small gastrin response from 28±3 to 39±5 pmol per liter (mean ±SEM, P < 0.01). Intravenous injection or prolonged infusion of gastrin increased the concentration of insulin in peripheral venous blood to a maximum within 2 min followed by a decline to basal levels after a further 10 min. The minimum dose required to induce a significant insulin response (31.2 ng gastrin per kg) increased the gastrin level in serum above the physiologic range. Maximum effect was obtained with 500 ng gastrin per kg. When 15.6 ng (7.1 pmol) gastrin per kg body weight and 25 g glucose were injected simultaneously, the glucose-induced insulin response was potentiated (from 2.32±0.33 to 4.33±0.98 nmol per liter per 20 min, P < 0.02), even though gastrin concentrations only increased to 71.2±6.6 pmol per liter. No effect, however, was noted on glucose disposal. 15.6 ng gastrin per kg given i.v. 30 min before an i.v. glucose tolerance test was without significant effect on the insulin response. The results indicate that gastrin can stimulate a rapid and short-lived release of insulin. In physiologic concentrations gastrin potentiates the glucose-stimulated insulin secretion and is without effect on basal insulin secretion. A small release of gastrin during oral glucose ingestion may to a limited extent contribute to the nonglycemic insulin secretion. During protein ingestion, gastrin probably stimulates insulin secretion significantly. Images PMID:4703228

  11. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats

    PubMed Central

    2011-01-01

    Background Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Methods Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Results Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Conclusions Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms. PMID:21526994

  12. 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

  13. Insulin-like Growth Factor 1-mediated Hyperthermia Involves Anterior Hypothalamic Insulin Receptors*

    PubMed Central

    Sanchez-Alavez, Manuel; Osborn, Olivia; Tabarean, Iustin V.; Holmberg, Kristina H.; Eberwine, James; Kahn, C. Ronald; Bartfai, Tamas

    2011-01-01

    The objective is to investigate the role of insulin-like growth factor 1 (IGF-1) in the regulation of core body temperature. Sequencing cDNA libraries from individual warm-sensitive neurons from the preoptic area (POA) of the hypothalamus, a region involved in the central control of thermoregulation, identified neurons that express both IGF-1 receptor (IGF-1R) and insulin receptor transcripts. The effects of administration of IGF-1 into the POA was measured by radiotelemetry monitoring of core temperature, brown adipose tissue (BAT) temperature, metabolic assessment, and imaging of BAT by positron emission tomography of 2-[18F]fluoro-2-deoxyglucose uptake combined with computed tomography. IGF-1 injection into the POA caused dose-dependent hyperthermia that could be blocked by pretreatment with the IGF-1R tyrosine kinase inhibitor, PQ401. The IGF-1-evoked hyperthermia involved activation of brown adipose tissue and was accompanied by a switch from glycolysis to fatty acid oxidation as a source of energy as shown by lowered respiratory exchange ratio. Transgenic mice that lack neuronal insulin receptor expression in the brain (NIRKO mice) were unable to mount the full hyperthermic response to IGF-1, suggesting that the IGF-1 mediated hyperthermia is partly dependent on expression of functional neuronal insulin receptors. These data indicate a novel thermoregulatory role for both IGF-1R and neuronal insulin receptors in IGF-1 activation of BAT and hyperthermia. These central effects of IGF-1 signaling may play a role in regulation of metabolic rate, aging, and the risk of developing type 2 diabetes. PMID:21330367

  14. Diabetes Patients' Experiences With the Implementation of Insulin Therapy and Their Perceptions of Computer-Assisted Self-Management Systems for Insulin Therapy

    PubMed Central

    Gude, Wouter T; Holleman, Frits; Hoekstra, Joost BL; Peek, Niels

    2014-01-01

    Background Computer-assisted decision support is an emerging modality to assist patients with type 2 diabetes mellitus (T2DM) in insulin self-titration (ie, self-adjusting insulin dose according to daily blood glucose levels). Computer-assisted insulin self-titration systems mainly focus on helping patients overcome barriers related to the cognitive components of insulin titration. Yet other (eg, psychological or physical) barriers could still impede effective use of such systems. Objective Our primary aim was to identify experiences with and barriers to self-monitoring of blood glucose, insulin injection, and insulin titration among patients with T2DM. Our research team developed a computer-assisted insulin self-titration system, called PANDIT. The secondary aim of this study was to evaluate patients’ perceptions of computer-assisted insulin self-titration. We included patients who used PANDIT in a 4-week pilot study as well as patients who had never used such a system. Methods In-depth, semi-structured interviews were conducted individually with patients on insulin therapy who were randomly recruited from a university hospital and surrounding general practices in the Netherlands. The interviews were transcribed verbatim and analyzed qualitatively. To classify the textual remarks, we created a codebook during the analysis, in a bottom-up and iterative fashion. To support examination of the final coded data, we used three theories from the field of health psychology and the integrated model of user satisfaction and technology acceptance by Wixom and Todd. Results When starting insulin therapy, some patients feared a lifelong commitment to insulin therapy and disease progression. Also, many barriers arose when implementing insulin therapy (eg, some patients were embarrassed to inject insulin in public). Furthermore, patients had difficulties increasing the insulin dose because they fear hypoglycemia, they associate higher insulin doses with disease progression

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

    PubMed

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

    2015-07-01

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

  16. Does salmon brain produce insulin?

    PubMed

    Plisetskaya, E M; Bondareva, V M; Duan, C; Duguay, S J

    1993-07-01

    To address the question whether fish brain can produce insulin, pink salmon (Oncorhynchus gorbusha) brains were extracted and processed according to the procedure developed for purification of pancreatic insulin (Rusakov and Bondareva, 1979). Biological and immunological activity of the resulting material was evaluated respectively by a cartilage sulfation assay and by radioimmunoassay homologous for salmon insulin. Preparations from salmon brain stimulated the [35S]sulfate uptake into salmon branchial cartilage with a potency comparable to pure mammalian or salmon insulins but lower than that of mammalian insulin-like growth factor (IGF-I). In contrast, only trace amounts of radioimmunoreactive insulin could be detected by homologous radioimmunoassay. To determine whether insulin mRNA was present in salmon brain, primers specific for salmon proinsulin and salmon prepro-IGF-I were designed to amplify corresponding cDNA regions by reverse transcriptase-PCR. Insulin mRNA was found only in the endocrine pancreas (Brockmann body) while IGF-I mRNA was detected in the brain, liver, and the Brockmann body. Our results suggest that in fish pancreatic-type insulin is most likely produced only in the endocrine pancreas and then transported to the brain through blood/cerebrospinal fluid system. However, it does not exclude a possibility that some yet unknown insulin-like substances may be expressed in the neural system of ectotherm vertebrates.

  17. 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.

  18. Treating insulin resistance: future prospects.

    PubMed

    Bailey, Clifford J

    2007-03-01

    Insulin resistance typically reflects multiple defects of insulin receptor and post-receptor signalling that impair a diverse range of metabolic and vascular actions. Many potential intervention targets and compounds with therapeutic activity have been described. Proof of principle for a non-peptide insulin mimetic has been demonstrated by specific activation of the intracellular B-subunit of the insulin receptor. Potentiation of insulin action has been achieved with agents that enhance phosphorylation and prolong the tyrosine kinase activity of the insulin receptor and its protein substrates after activation by insulin. These include inhibitors of phosphatases and serine kinases that normally prevent or terminate tyrosine kinase signalling. Additional approaches involve increasing the activity of phosphatidylinositol 3-kinase and other downstream components of the insulin signalling pathways. Experimental interventions to remove signalling defects caused by cytokines, certain adipocyte hormones, excess fatty acids, glucotoxicity and negative feedback by distal signalling steps have also indicated therapeutic possibilities. Several hormones, metabolic enzymes, minerals, co-factors and transcription co-activators have shown insulin-sensitising potential. Since insulin resistance affects many metabolic and cardiovascular diseases, it provides an opportunity for simultaneous therapeutic attack on a broad front.

  19. Vasopressin pressor antagonist injected centrally reverses behavioral effects of peripheral injection of vasopressin, but only at doses that reverse increase in blood pressure.

    PubMed

    Lebrun, C; Le Moal, M; Koob, G F; Bloom, F E

    1985-06-01

    Previous work in rats (Ader, R. and De Wied, D., Psychon. Sci., 29 (1972) 46-48) has established that subcutaneously (s.c.) injected arginine vasopressin (AVP) prolongs extinction of active avoidance and that this effect could be prevented by pretreatment with the vasopressin antagonist analog [1-deaminopenicillamine, 2-(O-methyl)tyrosine]-beta-arginine vasopressin (dPtyr(Me)AVP). The purpose of the present study was to determine if peripherally administered AVP acts via a peripheral blood pressure effect or by a direct action in the central nervous system. We therefore tested the effects of the antagonist injected intracerebroventricularly (i.c.v.) on the prolongation of active avoidance and on blood pressure effects of s.c. injected AVP. The antagonist (i.c.v.) blocked the behavioral effects of systemically injected AVP only at dose sufficient to block the peripherally mediated pressor response of systemically administered AVP. The results show that peripherally injected AVP acts on peripheral systems and support our hypothesis that the peripheral visceral action of AVP contributed significantly to its behavioral action.

  20. Coated vesicles participate in the receptor-mediated endocytosis of insulin

    PubMed Central

    1983-01-01

    We have purified coated vesicles from rat liver by differential ultracentrifugation. Electron micrographs of these preparations reveal only the polyhedral structures typical of coated vesicles. SDS PAGE of the coated vesicle preparation followed by Coomassie Blue staining of proteins reveals a protein composition also typical of coated vesicles. We determined that these rat liver coated vesicles possess a latent insulin binding capability. That is, little if any specific binding of 125I-insulin to coated vesicles is observed in the absence of detergent. However, coated vesicles treated with the detergent octyl glucoside exhibit a substantial specific 125I-insulin binding capacity. We visualized the insulin binding structure of coated vesicles by cross- linking 125I-insulin to detergent-solubilized coated vesicles using the bifunctional reagent disuccinimidyl suberate followed by electrophoresis and autoradiography. The receptor structure thus identified is identical to that of the high-affinity insulin receptor present in a variety of tissues. We isolated liver coated vesicles from rats which had received injections of 125I-insulin in the hepatic portal vein. We found that insulin administered in this fashion was rapidly and specifically taken up by liver coated vesicles. Taken together, these data are compatible with a functional role for coated vesicles in the receptor-mediated endocytosis of insulin. PMID:6131074

  1. Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice.

    PubMed

    Zhou, Bo; Li, Huixia; Liu, Jiali; Xu, Lin; Guo, Qinyue; Sun, Hongzhi; Wu, Shufang

    2015-12-01

    Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of PGRN in vivo and the underlying role of progranulin in adipose insulin resistance involving the autophagy mechanism is not fully understood. In this study, mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin sensitivity, remarkable adipose autophagy as well as attenuated insulin signaling via inhibition of mammalian target of rapamycin (mTOR) pathway. Furthermore, blockade of tumor necrosis factor receptor 1 (TNFR1) by TNFR1BP-Fc injection resulted in the restoration of impaired insulin sensitivity and insulin signaling induced by PGRN. Consistent with these findings in vivo, PGRN treatment induced defective insulin signaling, abnormal autophagic and mitochondrial activity in cultured adipocytes, while such effects were nullified by the blockade of TNFR1. In addition, PGRN-deficient adipocytes were more refractory to tunicamycin- or dexamethasone-induced insulin resistance, indicating the causative role of the TNFR1 pathway in the action of PGRN. Collectively, our findings support the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing autophagy via the TNFR1-dependent mechanism.

  2. Sustained prolonged topical delivery of bioactive human insulin for potential treatment of cutaneous wounds.

    PubMed

    Hrynyk, Michael; Martins-Green, Manuela; Barron, Annelise E; Neufeld, Ronald J

    2010-10-15

    Skin damaged by heat, radiation, or chemical exposure is difficult to treat and slow to heal. Indeed full restoration of the tissue is difficult to obtain. Sub-dermal insulin injection was recently shown to stimulate wound healing of the skin by accelerating wound closure, stimulating angiogenesis and inducing a regenerative process of healing. We have developed a topical delivery vehicle that is capable of releasing therapeutic levels of bioactive insulin for several weeks with the potential to stimulate and sustain healing. By encapsulating the crystalline form of insulin within poly(d,l-lactide-co-glycolide) microspheres, we succeeded in stabilizing and then releasing bioactive insulin for up to 25 days. To measure bioactivity we used Rat L6 myofibroblasts, stimulated them with this slow release insulin and determined activation of the receptors on the cell surface by quantifying AKT phosphorylation. There was only a minor and gradual decrease in AKT phosphorylation over time. To determine whether the slow release insulin could stimulate keratinocyte migration, wounding was simulated by scratching confluent cultures of human keratinocytes (HaCaT). Coverage of the scratch "wounds" was significantly faster in the presence of insulin released from microspheres than in the insulin-free control. Extended and sustained topical delivery of active insulin from a stable protein crystal-based reservoir shows promise in promoting tissue healing.

  3. Sustained prolonged topical delivery of bioactive human insulin for potential treatment of cutaneous wounds.

    PubMed

    Hrynyk, Michael; Martins-Green, Manuela; Barron, Annelise E; Neufeld, Ronald J

    2010-10-15

    Skin damaged by heat, radiation, or chemical exposure is difficult to treat and slow to heal. Indeed full restoration of the tissue is difficult to obtain. Sub-dermal insulin injection was recently shown to stimulate wound healing of the skin by accelerating wound closure, stimulating angiogenesis and inducing a regenerative process of healing. We have developed a topical delivery vehicle that is capable of releasing therapeutic levels of bioactive insulin for several weeks with the potential to stimulate and sustain healing. By encapsulating the crystalline form of insulin within poly(d,l-lactide-co-glycolide) microspheres, we succeeded in stabilizing and then releasing bioactive insulin for up to 25 days. To measure bioactivity we used Rat L6 myofibroblasts, stimulated them with this slow release insulin and determined activation of the receptors on the cell surface by quantifying AKT phosphorylation. There was only a minor and gradual decrease in AKT phosphorylation over time. To determine whether the slow release insulin could stimulate keratinocyte migration, wounding was simulated by scratching confluent cultures of human keratinocytes (HaCaT). Coverage of the scratch "wounds" was significantly faster in the presence of insulin released from microspheres than in the insulin-free control. Extended and sustained topical delivery of active insulin from a stable protein crystal-based reservoir shows promise in promoting tissue healing. PMID:20691251

  4. Intranasal Insulin Therapy for Cognitive Impairment and Neurodegeneration: Current State of the Art

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Introduction Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also minimize potentially hazardous off-target effects. Areas covered This review covers the role of intra-nasal insulin therapy for cognitive impairment and neurodegeneration, particularly Alzheimer's disease. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The author provides evidence that brain insulin resistance is an important and early abnormality in Alzheimer's disease, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert Opinion Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival, and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy, and specificity of intranasal insulin therapy. PMID:24215447

  5. Effective Enhancement of Hypoglycemic Effect of Insulin by Liver-Targeted Nanoparticles Containing Cholic Acid-Modified Chitosan Derivative.

    PubMed

    Zhang, Zhe; Cai, Huanxin; Liu, Zhijia; Yao, Ping

    2016-07-01

    Liver is responsible for the balance of blood glucose level. In this study, cholic acid and N-(2-hydroxy)-propyl-3-trimethylammonium chloride modified chitosan (HTCC-CA) was used as a liver-targeted vehicle for insulin delivery. A novel approach was developed to effectively load insulin by mixing insulin and HTCC-CA in 50% ethanol and water mixed solvent at pH 2 and then dialysis against pH 7.4 phosphate buffer subsequently against water. The insulin-loaded HTCC-CA nanoparticles have an average diameter of 86 nm and insulin loading efficiency of 98.7%. Due to random distribution of the hydrophobic cholic acid groups in HTCC-CA, some of the cholic acid groups located on the nanoparticle surface. Compared with free insulin, the nanoparticles increased in vitro cellular uptake of insulin to 466%, and the nanoparticles accumulated in liver for more time after subcutaneous injection into mice. The therapy for diabetic rats displayed that the nanoparticles increased the pharmacological bioavailability of insulin to 475% relative to free insulin, and the nanoparticles could maintain the hypoglycemic effect for more than 24 h. This study demonstrates that the nanoparticles with cholic acid groups on their surface possess liver-targeted property and biocompatible insulin-loaded HTCC-CA nanoparticles can effectively enhance the hypoglycemic effect of insulin. PMID:27266268

  6. Clinical Use and Evaluation of Insulin Pens

    PubMed Central

    Ginsberg, Barry H.

    2015-01-01

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

  7. 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

  8. Use of an artificial pancreas as a tool to determine subcutaneous insulin doses in juvenile diabetes.

    PubMed

    Lambert, A E; Buysschaert, M; Lambotte, L

    1979-01-01

    The present study was undertaken to examine the feasibility of determining the most appropriate subcutaneous insulin treatment in unstable diabetes on the basis of the circadian hormonal profile delivered by an artificial pancreas. The metabolic control of 11 brittle diabetic subjects, as assessed by the M value and the MAGE index (used as indexes of blood glucose control and of glycemic fluctuations, respectively), was compared during a 5-day period before and after a 24-h connection to the artificial pancreas. The usual insulin treatment was continued to that day. Examination of the insulin pattern revealed by the artificial pancreas suggested that a valid scheme for subsequent treatment should consist of two daily injections of a mixture of short-acting and intermediate-acting insulins, which was administered to the patients beginning with the injection given after the artificial pancreas onwards. The new insulin regimen was characterized by a total daily dose that increased from 0.93 +/- 0.10 to 1.20 +/- 0.10 U/kg body weight (mean +/- SEM; P less than 0.005) as well as by a higher proportion of the dose given as regular insulin (37.1 +/- 6.9% before vs. 56.0 +/- 2.1% after; P less than 0.05). These changes led to a better control of blood glucose in 10 patients, as evidenced by a decrease of both the M value and the mean of all blood glucose levels. The mean MAGE index was not decreased, however, by the new insulin program, thereby suggesting that the lability of the disease remained unabated. These results indicate that subcutaneous treatment consisting of two daily injections of regular and intermediate-acting insulins and comprising 50 to 60% of the former could improve the metabolic control in unstable diabetes. The artifical pancreas provided a rapid and simple means to determine the appropriate doses for each type of insulin.

  9. Extrapancreatic insulin effect of glibenclamide.

    PubMed

    Mulder, H; Schopman, W; van der Lely, A J

    1991-01-01

    In eight patients with uncomplicated non insulin dependent diabetes mellitus, serum insulin levels, serum C-peptide levels and blood glucose levels were measured before and after oral administration of glibenclamide 0.1 mg/kg body weight and a test meal, or after a test meal alone. The rise in serum insulin levels persisted longer after glibenclamide. The initial rise in serum insulin was of the same magnitude in both situations, as was the rise in serum C-peptide levels during the entire 5 h study. It is concluded that glibenclamide is able to maintain a more prolonged increase in serum insulin levels by inhibiting the degradation of insulin in the vascular endothelial cells of the liver. The inhibition contributes to the blood glucose lowering effect of glibenclamide. PMID:1904820

  10. Hip joint injection

    MedlinePlus

    ... injected so the provider can see where to place the medicine. The steroid medicine is slowly injected into the joint. After the injection, you will remain on the table for another 5 to 10 minutes or so. ...

  11. Simulatory effect of porcine insulin on noradrenaline secretion in guinea-pig ileum myenteric nerve terminals

    PubMed Central

    Cheng, Juei-Tang; Hung, Chen-Road; Lin, Ming-I

    1997-01-01

    The effect of insulin on the release of noradrenaline (NA) from nerve terminals was investigated in isolated ileal synaptosomes of guinea-pig. Release was determined as the amount of NA, quantified by h.p.l.c.-electrochemical detection, from samples incubated with insulin minus that in parallel blanks treated with some volume of vehicle.Porcine insulin stimulated the secretion of NA in a concentration-dependent manner from 0.01 i.u. ml−1, while the value of lactate dehydrogenase in the incubated medium was not influenced by insulin.The presence of insulin receptors in this preparation was illustrated by immunoblotting with insulin receptor monoclonal antibodies.The release of NA by insulin was reduced by guanethidine and bretylium and it was markedly lowered in the samples obtained from guinea-pigs that had received an intraperitoneal injection of DSP-4, the noradrenergic neurotoxin.Tetrodotoxin attenuated the action of insulin at concentrations sufficient to block sodium channels. The depolarizing effect of insulin on the membrane potential was also illustrated by a concentration-dependent increase in the fluorescence of bisoxonol, a potential-sensitive dye.The action of insulin was attenuated by removal of calcium chloride from the bathing medium. The induction of calcium ion influx by insulin into the synaptosomes is supported by the inhibitory effects of the calcium channel blockers ω-conotoxin GVIA (for the N-type channels) and nifedipine (for the L-type channels).These findings suggest that insulin can stimulate NA release from noradrenergic terminals via activation of calcium influx. PMID:9146881

  12. Protein Crystal Recombinant Human Insulin

    NASA Technical Reports Server (NTRS)

    1994-01-01

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

  13. Effect of patient-selected intensive insulin therapy on quality of life.

    PubMed

    Chantelau, E; Schiffers, T; Schütze, J; Hansen, B

    1997-02-01

    The purpose of the study was to assess quality of life in patients with IDDM in relation to the type of insulin therapy. Two patient cohorts were studied. In cohort A, 77 patients deliberately intensified their traditional insulin injection therapy from up to two daily injections with syringe to multiple daily injections with insulin-pen; in cohort B, 55 patients changed from intensive therapy with pen to insulin pump-treatment (CSII). The therapeutic regimens were changed during a 5-day in-patient treatment and teaching course. The DCCT questionnaire was applied before and up to 6 months after changing of therapy. Treatment satisfaction increased after intensification of insulin therapy in both groups, mainly due to greater flexibility with leisure-time activities, and with the diet. Pump-users reported reduced problems with hypoglycemia (P < 0.02). HbA1c indicating acceptable metabolic control already before the study, remained unchanged. Therapy-associated inconvenience, mainly in association with lifestyle, improved in IDDM patients deliberately intensifying their insulin therapy by pens or pumps (CSII). Pump-treatment, rather than pen-therapy, conferred particular protection from hypoglycaemia.

  14. Unlocking the opportunity of tight glycaemic control. Inhaled insulin: safety.

    PubMed

    Brain, Joseph D

    2005-11-01

    Clinical studies of inhaled insulins suggest that pulmonary delivery is well tolerated, with a level of safety comparable to that of subcutaneous (SC) insulin. Questions about the safety of Exubera focus primarily on the lungs, which are probably exposed to two to three times more insulin than an SC injection site. Pulmonary function tests (forced expiratory volume in 1 s and carbon monoxide-diffusing capacity) are routinely included as primary endpoints in Exubera clinical trials. Completed phase 2 and 3 studies up to 4 years in duration indicate that the differences over time in pulmonary function changes between patients treated with Exubera and control patients are small, non-progressive, clinically insignificant and reverse after discontinuation of Exubera therapy. However, it would be useful to understand the physiologic mechanisms responsible for these changes, and ongoing studies should continue to monitor the effects of inhaled insulin on pulmonary function and other parameters in patients with diabetes. In clinical trials of patients with type 1 or 2 diabetes who were treated with Exubera, the only significant clinical adverse effect was cough. This was generally characterized as mild to moderate in severity, decreased over time and was not associated with declines in lung function. Thus, insulin administration via the lung appears to be generally safe in patients with type 1 or 2 diabetes. PMID:16135134

  15. Effect of vanadium on insulin sensitivity and appetite.

    PubMed

    Wang, J; Yuen, V G; McNeill, J H

    2001-06-01

    Vanadium, a potent nonselective inhibitor of protein tyrosine phosphatases, has been shown to mimic many of the metabolic actions of insulin both in vivo and in vitro. The mechanism(s) of the effect of vanadium on the decrease in appetite and body weight in Zucker fa/fa rats, an insulin-resistant model, is still unclear. Because insulin may inhibit hypothalamic neuropeptide Y (NPY), which is known to be related to appetite, and increase leptin secretion in adipose tissue, we studied the possibility that the changes in appetite produced by vanadium may be linked to altered NPY levels in the hypothalamus. We also examined effects of vanadium on leptin. Zucker lean and fatty rats were chronically treated with bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, in the drinking water. Plasma and adipose tissue leptin levels were measured by radioimmunoassay and immunoblotting, respectively. Hypothalamic NPY mRNA and peptide levels were measured using in situ hybridization and immunocytochemistry, respectively. BMOV treatment significantly reduced food intake, body fat, body weight, plasma insulin levels, and glucose levels in fatty Zucker rats. Fifteen minutes after insulin injection (5 U/kg, intravenous [IV]), circulating leptin levels (+100%) and adipose leptin levels (+60%) were elevated in BMOV-treated fatty rats, although these effects were not observed in untreated fatty rats. NPY mRNA levels in the arcuate nucleus (ARC) (-29%), NPY peptide levels in ARC (-31%), as well as in the paraventricular nucleus (PVN) (-37%) were decreased with BMOV treatment in these fatty rats. These data indicate that BMOV may increase insulin sensitivity in adipose tissue and decrease appetite and body fat by decreasing NPY levels in the hypothalamus. BMOV-induced reduction in appetite and weight gain along with normalized insulin levels in models of obesity, suggest its possible use as a therapeutic agent in obesity.

  16. Biological activity of insulin in GMO gels and the effect of agitation.

    PubMed

    Sadhale, Y; Shah, J C

    1999-11-25

    Glyceryl monooleate (GMO)-water cubic phase gel was previously shown to protect insulin from agitation induced aggregation. However, it is not known if insulin is biologically active in the gel and what effect agitation has on insulin in the gel. Therefore, the objective was to determine the stability of insulin in cubic phase gel in terms of its biological activity in a suitable animal model such as Sprague-Dawley rats. Effect of agitation on biological activity of insulin in cubic phase GMO gel was determined by subcutaneous injections of the agitated and non-agitated gels to two groups of previously fasted rats and measuring the effect on their blood glucose levels. Two groups of rats administered with agitated insulin solution and normal saline were used as controls. The biological activity of insulin was evaluated by comparing AAC (area above the blood glucose level-time curve, in %-h), C(max) (maximum % decrease in blood glucose levels) and t(max) (time required to attain C(max), in h) values for the four groups of rats. Since cubic phase gel is highly viscous, therapeutic equivalency of insulin in the lamellar phase gel, which converts in situ into cubic phase gel, was compared to insulin solution with normal saline as the control, using AAC, C(max) and t(max) of the blood glucose profile. Insulin was biologically active in both agitated and non-agitated gels; however, upon agitation, insulin in solution totally lost its hypoglycemic activity. Agitation of insulin in the cubic phase gel was seen to have very little deleterious effect on its biological activity. Insulin in the lamellar phase gel was not only biologically active but also therapeutically equivalent to insulin solution based on AAC (327.9+/-100.8 and 431.7+/-113.3), C(max) (57. 1+/-7.0 and 70.2+/-6.5) and t(max) (2.8+/-0.7 and 4.0+/-1.7) for the lamellar phase gel and insulin solution, respectively (no significant difference, P0.05). In summary, GMO cubic phase gel protected insulin from

  17. The importance of patient compliance with insulin pens: how can a new user-friendly pen help?

    PubMed

    Pafili, Kalliopi; Papanas, Nikolaos

    2014-05-01

    FlexTouch® (FT) is a new prefilled insulin pen with the unique characteristic of no extendable push button at any dose setting and consequently a low activation force. Its technical features along with health care professionals' and patients' preferences in comparison to other traditionally used devices for insulin delivery have already been investigated. Recently, a study of injection force and accuracy using FT in the delivery of new basal insulin has compared FT with the insulin pens KwikPen® and SoloStar® and has shown that FT exhibits preciseness in insulin delivery of all insulin formulations and a significantly lower activation force than the other two insulin injectors. Despite the very promising characteristics of this new device, important questions remain to be answered, mainly the possible promotion of treatment adherence and the notion of confidence in self-administration of insulin. Moreover, an analysis of patients' perception on injecting higher doses with FT in comparison to other insulin injectors would be useful.

  18. Effect of insulin on weight loss and tumour growth in a cachexia model.

    PubMed Central

    Beck, S. A.; Tisdale, M. J.

    1989-01-01

    A comparison has been made between the effects of daily insulin injection and a ketogenic diet on weight loss and tumour weight in an experimental model of cancer cachexia (MAC16). Weight loss associated with the MAC16 tumour was significantly reduced both by a ketogenic diet (80% MCT) and by daily insulin injections without an increase in either food or water consumption. Animals fed the 80% MCT diet had a significantly reduced tumour weight compared with controls fed a normal laboratory diet, while in animals administered 20 U insulin kg-1 day-1 the tumour weight was 50% greater than in saline infused controls. The stimulation of tumour growth by insulin was counteracted by the inclusion of 3-hydroxybutyrate in the drinking water without any alteration in the extent of weight loss. Depletion of both carcass fat and muscle dry weight in animals bearing the MAC16 tumour was reversed in animals administered either insulin or an 80% MCT diet. Animals bearing the MAC16 tumour had a reduced nitrogen balance compared with non-tumour-bearing controls, mainly due to excess urea excretion, and this was reversed towards control values in animals fed an 80% MCT diet, but not in animals administered insulin. These results suggest that a ketogenic diet is more effective than insulin administration in reversing the cachectic process and has the advantage of a concomitant reduction in tumour weight. PMID:2736199

  19. An investigation of bloodborne pathogen transmission due to multipatient sharing of insulin pens.

    PubMed

    Hakre, Shilpa; Upshaw-Combs, Donna R; Sanders-Buell, Eric E; Scoville, Stephanie L; Kuper, Joshua D; Jagodzinski, Linda L; Bradfield, Andrea N; Davison, Dinae C; Callis, William G; Owens, Angela B; Michael, Nelson L; O'Connell, Robert J; Peel, Sheila A; Gardner, John W; Thompson, Nicola D; Hu, Dale J; Kim, Jerome H; Tovanabutra, Sodsai; Scott, Paul T; LaFon, Sandra G

    2012-08-01

    On January 30, 2009, nursing staff at a military hospital in Texas reported that single-patient use insulin pens were used on multiple patients. An investigation was initiated to determine if patient-to-patient bloodbome transmission occurred from the practice. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) testing was offered to patients hospitalized from August 2007 to January 2009 and prescribed insulin pen injections. Virus from HCV-infected patients' sera was sequenced and compared for relatedness. An anonymous survey was administered to nurses. Of 2,113 patients prescribed insulin pen injections, 1,501 (71%) underwent testing; 6 (0.4%) were HIV positive, 6 (0.4%) were hepatitis B surface antigen positive, and 56 (3.7%) had HCV antibody. No viral sequences from 10 of 28 patients with newly diagnosed and 12 of 28 patients with preexisting HCV infection were closely related. Of 54 nurses surveyed, 74% reported being trained on insulin pen use, but 24% believed nurses used insulin pens on more than one patient. We found no clear evidence of bloodborne pathogen transmission. Training of hospital staff on correct use of insulin pens should be prioritized and their practices evaluated. Insulin pens should be more clearly labeled for single-patient use.

  20. Central injection of CDP-choline suppresses serum ghrelin levels while increasing serum leptin levels in rats.

    PubMed

    Kiyici, Sinem; Basaran, Nesrin Filiz; Cavun, Sinan; Savci, Vahide

    2015-10-01

    In this study we aimed to test central administration of CDP-choline on serum ghrelin, leptin, glucose and corticosterone levels in rats. Intracerebroventricular (i.c.v.) 0.5, 1.0 and 2.0 µmol CDP-choline and saline were administered to male Wistar-Albino rats. For the measurement of serum leptin and ghrelin levels, blood samples were obtained baseline and at 5, 15, 30, 60 and 120 min following i.c.v. CDP-choline injection. Equimolar doses of i.c.v. choline (1.0 µmol) and cytidine (1.0 µmol) were administered and measurements were repeated throughout the second round of the experiment. Atropine (10 µg) and mecamylamine (50 µg) were injected intracerebroventricularly prior to CDP-choline and measurements repeated in the third round of the experiment. After 1 µmol CDP-choline injection, serum ghrelin levels were suppressed significantly at 60 min (P=0.025), whereas serum leptin levels were increased at 60 and 120 min (P=0.012 and P=0.017 respectively). CDP-choline injections also induced a dose- and time-dependent increase in serum glucose and corticosterone levels. The effect of choline on serum leptin and ghrelin levels was similar with CDP-choline while no effect was seen with cytidine. Suppression of serum ghrelin levels was eliminated through mecamylamine pretreatment while a rise in leptin was prevented by both atropine and mecamylamine pretreatments. In conclusion; centrally injected CDP-choline suppressed serum ghrelin levels while increasing serum leptin levels. The observed effects following receptor antagonist treatment suggest that nicotinic receptors play a role in suppression of serum ghrelin levels,whereas nicotinic and muscarinic receptors both play a part in the increase of serum leptin levels.

  1. Determination of insulin in humans with insulin-dependent diabetes mellitus patients by HPLC with diode array detection.

    PubMed

    Yilmaz, Bilal; Kadioglu, Yucel; Capoglu, Ilyas

    2012-08-01

    A simple and reliable high-performance liquid chromatographic method with diode array detection has been developed and validated for the determination of insulin in human plasma. A good chromatographic separation was achieved on a C18 column with a mobile phase consisting of acetonitrile and 0.2M sodium sulfate (pH 2.4), 25:75 (v/v). Its flow rate was 1.2 mL/min. Calibration curve was linear within the concentration range of 0.15-25 µg/mL. Intra-day and inter-day relative standard deviations for insulin in human plasma were less than 6.3 and 8.5%, respectively. The limits of detection and quantification of insulin were 0.10 and 0.15 µg/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of insulin in eight insulin-dependent diabetes mellitus patients after subcutaneous injection of 25 IU of Actrapid HM.

  2. Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

    PubMed

    Zeng, Yi; Zhang, Le; Hu, Zhiping

    2016-01-01

    Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

  3. Action of a semi-synthetic human insulin preparation (30/70 NPH insulin Organon): comparison with another 30/70 NPH (Actraphane Novo).

    PubMed

    Gin, H; Nivet, A M; Morlat, P; Aubertin, J

    1989-01-01

    The action of a new semi-synthetic insulin preparation (30% soluble, 70% NPH insulin from Organon Laboratories Eragny sur Epte France) was studied in 6 healthy male volunteers using the euglycemic clamp technique (Biostator GCIIS) and compared with another 30/70 NPH (Actraphane Novo). Insulin levels, inhibition of C peptide secretion and glucose consumption were determined. There was a time lag between the maximum glucose need (167 +/- 18 mg/Kg/15 min at the 195th minute after the injection) and the peak plasma insulin level (98.3 +/- 8.5 uu/ml at the 105th minute following the injection). The maximum glucose need was followed by a slow fall in insulin levels with a duration of action of 17 hours. The total glucose need was the same as for Actraphane, although Actraphane had a slower action with a lower peak glucose need (144 +/- 18 mg/Kg/15 min at the 280th minute after injection). The two preparations had the same duration of action.

  4. Paediatrics, insulin resistance and the kidney.

    PubMed

    Marlais, Matko; Coward, Richard J

    2015-08-01

    Systemic insulin resistance is becoming more prevalent in the young due to modern lifestyles predisposing to the metabolic syndrome and obesity. There is also evidence that there are critical insulin-resistant phases for the developing child, including puberty, and that renal disease per se causes systemic insulin resistance. This review considers the factors that render children insulin resistant, as well as the accumulating evidence that the kidney is an insulin-responsive organ and could be affected by insulin resistance.

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

    PubMed Central

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

    2014-01-01

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

  6. Glucose and insulin metabolism in cirrhosis.

    PubMed

    Petrides, A S; DeFronzo, R A

    1989-01-01

    Glucose intolerance, overt diabetes mellitus, and insulin resistance are characteristic features of patients with cirrhosis. Insulin secretion, although increased in absolute terms, is insufficient to offset the presence of insulin resistance. The defect in insulin-mediated glucose disposal involves peripheral tissues, primarily muscle, and most likely reflects a disturbance in glycogen synthesis. Hepatic glucose production is normally sensitive to insulin; at present, it is unknown whether hepatic glucose uptake is impaired in cirrhosis. One of the more likely candidates responsible for the insulin-resistant state is insulin itself. The hyperinsulinemia results from three abnormalities: diminished hepatic extraction, portosystemic/intrahepatic shunting, and enhanced insulin secretion. PMID:2646365

  7. Beam Injection into RHIC

    NASA Astrophysics Data System (ADS)

    Fischer, W.; Hahn, H.; Mackay, W. W.; Tsoupas, N.

    1997-05-01

    During the RHIC sextant test in January 1997 beam was injected into a sixth of one of the rings for the first time. We describe the injection zone and its bottlenecks, the application program to steer the beam and the injection kickers. We report on the commissioning of the injection systems and on measurements of the kickers.

  8. Insulin Signaling and Heart Failure.

    PubMed

    Riehle, Christian; Abel, E Dale

    2016-04-01

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

  9. Insulin Signaling and Heart Failure.

    PubMed

    Riehle, Christian; Abel, E Dale

    2016-04-01

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

  10. Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

    PubMed

    Winkelman, L A; Overton, T R

    2013-01-01

    This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows

  11. Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

    PubMed

    Winkelman, L A; Overton, T R

    2013-01-01

    This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows

  12. Ginseng berry extract supplementation improves age-related decline of insulin signaling in mice.

    PubMed

    Seo, Eunhui; Kim, Sunmi; Lee, Sang Jun; Oh, Byung-Chul; Jun, Hee-Sook

    2015-04-01

    The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007). Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS)-1 (p = 0.047), and protein kinase B (AKT) (p = 0.037), were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1) (p = 0.036) and peroxisome proliferator-activated receptor gamma (PPARγ) (p = 0.032), which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice. PMID:25912041

  13. Insulin-induced localized lipoatrophy preceded by shingles (herpes zoster): a case report

    PubMed Central

    2014-01-01

    Introduction Localized involutional lipoatrophy of subcutaneous adipose tissue may develop due to subcutaneous injection of pharmaceutical preparations. The pathogenesis of this adverse drug reaction is unknown. The progression of localized involutional lipoatrophy ceases and occasionally it resolves after withdrawing the inducing agent. In case of localized involutional lipoatrophy due to subcutaneous insulin therapy, low-dose systemic corticosteroids may be curative despite ongoing insulin administration. Case presentation We report a recurrence of insulin-induced localized involutional lipoatrophy at the abdominal wall in a 57-year-old Caucasian woman with type-1 diabetes on continuous subcutaneous insulin infusion. The first episode of insulin-induced localized involutional lipoatrophy two years previously had been cured by oral prednisone. The recurrence was treated immediately with 10mg prednisone once daily for five months, and was cured thereafter. The insulin analog preparation (Humalog™) and the insulin pump equipment (Accu-Chek Spirit™) applied were the same during both episodes. Both episodes were preceded by a temporary disturbance of the immune balance (the first episode by vaccination, the second episode through shingles). Conclusions This case confirms that insulin-induced localized involutional lipoatrophy in type-1 diabetes can occur again, and can be cured by systemic corticosteroids. We suggest that temporary disturbance of the immune balance may trigger this transitory idiosyncratic reaction in a susceptible individual. PMID:24961832

  14. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    PubMed Central

    Seo, Eunhui; Kim, Sunmi; Lee, Sang Jun; Oh, Byung-Chul; Jun, Hee-Sook

    2015-01-01

    The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old) were maintained on a regular diet (CON) or a regular diet supplemented with 0.05% ginseng berry extract (GBD) for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016) and insulin resistance scores (HOMA-IR) (p = 0.012), suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007). Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS)-1 (p = 0.047), and protein kinase B (AKT) (p = 0.037), were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1) (p = 0.036) and peroxisome proliferator-activated receptor gamma (PPARγ) (p = 0.032), which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice. PMID:25912041

  15. Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats

    PubMed Central

    Dotzert, Michelle S.; Murray, Michael R.; McDonald, Matthew W.; Olver, T. Dylan; Velenosi, Thomas J.; Hennop, Anzel; Noble, Earl G.; Urquhart, Brad L.; Melling, C. W. James

    2016-01-01

    The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9–15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training. PMID:27197730

  16. Gestational diabetes mellitus: Non-insulin management.

    PubMed

    Magon, Navneet; Seshiah, V

    2011-10-01

    Gestational diabetes mellitus (GDM) complicates a substantial number of pregnancies. There is consensus that in patients of GDM, excellent blood glucose control, with diet and, when necessary, oral hypoglycemics and insulin results in improved perinatal outcomes, and appreciably reduces the probability of serious neonatal morbidity compared with routine prenatal care. Goals of metabolic management of a pregnancy complicated with GDM have to balance the needs of a healthy pregnancy with the requirements to control glucose level. Medical nutrition therapy is the cornerstone of therapy for women with GDM. Surveillance with daily self-monitoring of blood glucose has been found to help guide management in a much better way than blood glucose checking in labs and clinics, which tends to be less frequent. Historically, insulin has been the therapeutic agent of choice for controlling hyperglycemia in pregnant women. However, difficulty in medication administration with multiple daily injections, potential for hypoglycemia, and increase in appetite and weight make this therapeutic option cumbersome for many pregnant patients. Use of oral hypogycemic agents (OHAs) in pregnancy has opened new vistas for GDM management. At present, there is a growing acceptance of glyburide (glibenclamide) use as the primary therapy for GDM. Glyburide and metformin have been found to be safe, effective and economical for the treatment of gestational diabetes. Insulin, however, still has an important role to play in GDM. GDM is a window of opportunity, which needs to be seized, for prevention of diabetes in future life. Goal of our educational programs should be not only to improve pregnancy outcomes but also to promote healthy lifestyle changes for the mother that will last long after delivery. Team effort on part of obstetricians and endocrinologists is required to make "the diabetes capital of the world" into "the diabetes care capital of the world".

  17. Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations.

    PubMed

    Luippold, Gerd; Bedenik, Jessica; Voigt, Anke; Grempler, Rolf

    2016-01-01

    The chemical induction of diabetes with STZ has gained popularity because of the relative ease of rendering normal animals diabetic. Insulin substitution is required in STZ-rats in long-term studies to avoid ketoacidosis and consequently loss of animals. Aim of the present studies was to test different insulin preparations and different ways of administration in their ability to reduce blood glucose in STZ-induced diabetic rats. Single dosing of the long-acting insulin analogue glargine was able to dose-dependently reduce blood glucose over 4 h towards normoglycemia in STZ-treated rats. However, this effect was not sustained until 8 h post injection. A more sustained glucose-lowering effect was achieved using insulin-releasing implants. In STZ-rats, 1 insulin implant moderately lowered blood glucose levels 10 days after implantation, while 2 implants induced normoglycemia over the whole day. According to the glucose-lowering effect 1 as well as 2 insulin implants significantly reduced HbA1c measured after 26 days of implantation. In line with the improved glucose homeostasis due to the implants, urinary glucose excretion was also blunted in STZ-treated rats with 2 implants. Since diabetic nephropathy is one of the complications of longterm diabetes, renal function was characterized in the STZ-rat model. Increases in creatinine clearance and urinary albumin excretion resemble early signs of diabetic nephropathy. These functional abnormalities of the kidney could clearly be corrected with insulin-releasing implants 27 days after implantation. The data show that diabetic STZ-rats respond to exogenous insulin with regard to glucose levels as well as kidney parameters and a suitable dose of insulin implants for glucose control was established. This animal model together with the insulin dosing regimen is suitable to address diabetes-induced early diabetic nephropathy and also to study combination therapies with insulin for the treatment of type 1 diabetes. PMID:27253523

  18. Comparing the quality of life in insulin recipient and refusal patients with type 2 diabetes

    PubMed Central

    Khalili, Mitra; Sabouhi, Fakhri; Abazari, Parvaneh; Aminorroaya, Ashraf

    2016-01-01

    Background: Better control of blood sugar and reduction of diabetes complications through insulin therapy could convince people to choose this method. However, patients might refuse insulin therapy due to its painful injection, limitations in daily activities, and hypoglycemia. Thus, insulin therapy could have both positive and negative effects on patients’ quality of life (QOL). Therefore, the aim of this study was to compare the QOL of insulin recipient and insulin refusal patients with type 2 diabetes. Materials and Methods: This study was a descriptive and comparative research conducted on 126 patients; 63 were insulin recipients and 63 had refused insulin therapy. Participants were under the care of the Endocrine and Metabolism Research Center of Isfahan, Iran. Data were gathered using the Diabetes Quality of Life (DQOL) questionnaire. In this tool, higher scores indicated lower QOL in patients. Data were analyzed using independent t-test, analysis of covariance, Mann-Whitney, Chi-square, and Pearson and Spearman's correlation. Results: There was a significant difference (P < 0.001) between insulin recipient patients (mean = 2.02, SD = 0.31) and insulin refusal patients (mean = 1.74, SD = 0.41) in terms of mean QOL score. In addition, men and participants with higher educational levels reported a better QOL (P < 0.001). Conclusions: Results showed that insulin refusal patients had a better QOL. It seems that QOL is associated with the acceptance or refusal of insulin therapy. Therefore, enhancement of QOL could be related to all aspects of the disease, especially its treatment method and solving the therapeutic problems. PMID:27563316

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

    PubMed

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

    2016-08-01

    Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of β-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise β-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote β-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to

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

    PubMed

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

    2016-08-01

    Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of β-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise β-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote β-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to

  1. [Comparison of biosynthetic human insulin and purified pork insulin. Studies in insulin-resistant obese patients using the insulin suppression test].

    PubMed

    Richard, J L; Rodier, M; Cavalie, G; Lachkar, H; Orsetti, A; Monnier, L; Mirouze, J

    1986-02-01

    An insulin suppression test performed in random order with either biosynthetic human insulin or purified pork insulin was used to compare biological activity of these two insulins in obese patients suffering from varying degrees of glucose intolerance. Blood glucose curve, steady-state blood glucose levels, insulin sensitivity indices and steady-state plasma insulin levels were identical during the two sets of tests. Furthermore endogenous insulin and glucagon secretion were similarly suppressed. The insulin suppression test is a simple and rapid procedure to compare the biological activity of fast-acting insulins. Our results confirm the insulin-resistance in obesity and clearly show that biosynthetic human and porcine insulins have similar biological potency.

  2. Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects

    PubMed Central

    de la Peña, Amparo; Riddle, Matthew; Morrow, Linda A.; Jiang, Honghua H.; Linnebjerg, Helle; Scott, Adam; Win, Khin M.; Hompesch, Marcus; Mace, Kenneth F.; Jacobson, Jennie G.; Jackson, Jeffrey A.

    2011-01-01

    OBJECTIVE Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). RESEARCH DESIGN AND METHODS This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. RESULTS Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05). CONCLUSIONS Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes. PMID:21994429

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

    PubMed Central

    2013-01-01

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

  4. Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

    PubMed Central

    Gordon, Kathryn W.

    2014-01-01

    The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275–400 g) were infused with isotonic saline or insulin (3.75 mU·kg−1·min−1) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist dl-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. PMID:25475355

  5. Prevalence of Lipohypertrophy and Associated Risk Factors in Insulin-Treated Patients With Type 2 Diabetes Mellitus

    PubMed Central

    Al Ajlouni, Mo’men; Abujbara, Mousa; Batieha, Anwar; Ajlouni, Kamel

    2015-01-01

    Background: Secondary failure of oral hypoglycemic agents is common in patients with type 2 diabetes mellitus (T2DM); thus, patients often need insulin therapy. The most common complication of insulin treatment is lipohypertrophy (LH). Objectives: This study was conducted to estimate the prevalence of LH among insulin-treated patients with Patients with T2DM, to identify the risk factors for the development of LH, and to examine the association between LH and glycemic control. Patients and Methods: A total of 1090 patients with T2DM aged 20 to 89 years, who attended the diabetes clinics at the National Center for Diabetes, Endocrinology, and Genetics (NCDEG, Amman, Jordan) between October 2011 and January 2012, were enrolled. The presence of LH was examined by inspection and palpation of insulin injection sites at the time of the visit as relevant clinical and laboratory data were obtained. The LH was defined as a local tumor-like swelling of subcutaneous fatty tissue at the site of repeated insulin injections. Results: The overall prevalence of LH was 37.3% (27.4% grade 1, 9.7% grade 2, and 0.2% grade 3). The LH was significantly associated with the duration of diabetes, needle length, duration of insulin therapy, lack of systematic rotation of insulin injection sites, and poor glycemic control. Conclusions: The LH is a common problem in insulin-treated Jordanian patients with T2DM. More efforts are needed to educate patients and health workers on simple interventions such as using shorter needles and frequent rotation of the insulin injection sites to avoid LH and improve glycemic control. PMID:25926852

  6. The effect of insulin on plasma glucose concentrations, expression of hepatic glucose transporters and key gluconeogenic enzymes during the perinatal period in broiler chickens.

    PubMed

    Franssens, Lies; Lesuisse, Jens; Wang, Yufeng; Willems, Els; Willemsen, Hilke; Koppenol, Astrid; Guo, Xiaoquan; Buyse, Johan; Decuypere, Eddy; Everaert, Nadia

    2016-06-01

    Chickens have blood glucose concentrations that are twofold higher than those observed in mammals. Moreover, the insulin sensitivity seems to decrease with postnatal age in both broiler and layer chickens. However, little is known about the response of insulin on plasma glucose concentrations and mRNA abundance of hepatic glucose transporters 1, 2, 3, 8, 9 and 12 (GLUT1, 2, 3, 8, 9 and 12) and three regulatory enzymes of the gluconeogenesis, phosphoenolpyruvate carboxykinase 1 and 2 (PCK1 and 2) or fructose-1,6-biphosphatase 1 (FBP1) in chicks during the perinatal period. In the present study, broiler embryos on embryonic day (ED)16, ED18 or newly-hatched broiler chicks were injected intravenously with bovine insulin (1μg/g body weight (BW)) to examine plasma glucose response and changes in hepatic mRNA abundance of the GLUTs, PCK1 and 2 and FBP1. Results were compared with a non-treated control group and a saline-injected sham group. Plasma glucose levels of insulin-treated ED18 embryos recovered faster from their minimum level than those of insulin-treated ED16 embryos or newly-hatched chicks. In addition, at the minimum plasma glucose level seven hours post-injection (PI), hepatic GLUT2, FBP1 and PCK2 mRNA abundance was decreased in insulin-injected embryos, compared to sham and control groups, being most pronounced when insulin injection occurred on ED16. PMID:26723190

  7. The effect of insulin on plasma glucose concentrations, expression of hepatic glucose transporters and key gluconeogenic enzymes during the perinatal period in broiler chickens.

    PubMed

    Franssens, Lies; Lesuisse, Jens; Wang, Yufeng; Willems, Els; Willemsen, Hilke; Koppenol, Astrid; Guo, Xiaoquan; Buyse, Johan; Decuypere, Eddy; Everaert, Nadia

    2016-06-01

    Chickens have blood glucose concentrations that are twofold higher than those observed in mammals. Moreover, the insulin sensitivity seems to decrease with postnatal age in both broiler and layer chickens. However, little is known about the response of insulin on plasma glucose concentrations and mRNA abundance of hepatic glucose transporters 1, 2, 3, 8, 9 and 12 (GLUT1, 2, 3, 8, 9 and 12) and three regulatory enzymes of the gluconeogenesis, phosphoenolpyruvate carboxykinase 1 and 2 (PCK1 and 2) or fructose-1,6-biphosphatase 1 (FBP1) in chicks during the perinatal period. In the present study, broiler embryos on embryonic day (ED)16, ED18 or newly-hatched broiler chicks were injected intravenously with bovine insulin (1μg/g body weight (BW)) to examine plasma glucose response and changes in hepatic mRNA abundance of the GLUTs, PCK1 and 2 and FBP1. Results were compared with a non-treated control group and a saline-injected sham group. Plasma glucose levels of insulin-treated ED18 embryos recovered faster from their minimum level than those of insulin-treated ED16 embryos or newly-hatched chicks. In addition, at the minimum plasma glucose level seven hours post-injection (PI), hepatic GLUT2, FBP1 and PCK2 mRNA abundance was decreased in insulin-injected embryos, compared to sham and control groups, being most pronounced when insulin injection occurred on ED16.

  8. Effect of exogenous insulin on plasma and follicular insulin-like growth factor I, insulin-like growth factor binding protein activity, follicular oestradiol and progesterone, and follicular growth in superovulated Angus and Brahman cows.

    PubMed

    Simpson, R B; Chase, C C; Spicer, L J; Vernon, R K; Hammond, A C; Rae, D O

    1994-11-01

    Angus (n = 14) and Brahman (n = 14) cows were used to evaluate the effects of insulin administered concomitantly with FSH in a superovulation regimen. Cows were allotted to four pen replicates by treatment and breed, and received FSH (i.m.) twice a day for 5 consecutive days (first day of injections = day 0 of study) plus concomitant administration of either saline (control) or long-acting bovine insulin (0.25 iu kg-1 body mass; s.c.). Blood samples were collected at intervals of 6 h during the injection period and analysed for plasma insulin, glucose, insulin-like growth factor I (IGF-I) and IGF-I binding protein (IGFBP) activity. Cows were ovariectomized on day 5. The number and diameter of follicles were recorded. Follicular fluid was aspirated for determination of IGF-I, IGFBP activity, oestradiol and progesterone. Mean plasma concentration of glucose was lower in insulin-treated than in control cows averaged over days 1-5 (56 +/- 3 versus 82 +/- 3 mg dl-1; P < 0.01). Plasma concentration of IGF-I and IGFBP activity were not affected (P > 0.10) by treatment, but were higher in Brahman than in Angus cows (IGF-I: 41 +/- 6 versus 19 +/- 6 ng ml-1, P < 0.05; IGFBP activity: 17.5 +/- 0.4 versus 15.8 +/- 0.04% (10 microliters)-1; P < 0.03). Insulin treatment did not affect the number of small (1.0-3.9 mm), medium (4.0-7.9 mm) or large (> or = 8.0 mm) follicles. Brahman cows had a greater (P < 0.01) number of medium and total follicles (19.4 +/- 2.5 and 60.5 +/- 5.5, respectively) than did Angus cows (7.5 +/- 2.6 and 30.5 +/- 5.6, respectively). Diameter of large follicles was greater in insulin-treated than in control cows (11.4 +/- 0.2 versus 10.6 +/- 0.1 mm; P < 0.05). Follicular fluid IGF-I concentration in large follicles was higher in insulin-treated Brahman cows (60 +/- 2 ng ml-1) than in control Brahman cows (37 +/- 2 ng ml-1), but was lower in insulin-treated Angus cows (31 +/- 3 ng ml-1) than in control Angus cows (38 +/- 2 ng ml-1; treatment x breed

  9. [Abdomen pendulum and subcutaneous injections: the complications. Two case reports].

    PubMed

    Benhaim, T; Sinna, R; Garson, S; Boloorchi, A; Crozet, C; Robbe, M

    2007-06-01

    The authors present the complications due to subcutaneous injections on two patients suffering from morbid obesity with an abdomen pendulum. In the first case, injections of heparin of low molecular weight at curative dose, for treatment of a pulmonary embolism, have been complicated with a giant abdominal wall haematoma, the biggest ever reported. The initial treatment was insufficient so we had to practice a dermolipectomy to take off the haematoma of four litters. In the second case, insulin injections were complicated with cellulitis of the abdominal wall and a surgical treatment has been practiced in emergency. The first case reminds us the importance to change the sites of injections and to accommodate the dose, surgical treatment staying as simple as possible. The second case allows us to report a rare complication, not often published but known with obese patients. These two cases illustrate the importance of therapeutic education of the patient and the fact that a simple injection can be life threatening.

  10. Insulin self-association and the relationship to pharmacokinetics and pharmacodynamics.

    PubMed

    DeFelippis, M R; Chance, R E; Frank, B H

    2001-01-01

    The treatment of type 1 diabetes requires multiple, daily injections of insulin. While many improvements involving formulation adjustments have been made in an attempt to optimize therapy, clinical experience indicates that the commercially available insulin preparations used for treatment have significant limitations. One principal deficiency relates to poor simulation of the physiological insulin secretion pattern, making achieving normalization of blood glucose concentrations difficult. Endogenous insulin secretion in nondiabetic subjects is characterized by a pulsatile profile that displays multiple, meal-stimulated phases and low basal concentrations between meals and overnight. Optimal diabetes therapy, therefore, requires insulin preparations that display a rapid onset of action with corresponding rapid clearance to provide for meal ingestion as well as preparations that can maintain a sustained, peakless profile for basal requirements. Recent efforts in pharmaceutical research have used the concept of rational-based design of the insulin molecule in an attempt to produce preparations that display more ideal pharmacological profiles. Using detailed structural information obtained from X-ray crystallographic studies to guide design strategies and exploit the nonrestrictive synthetic capabilities of recombinant DNA technology, researchers have prepared a number of insulin analogs that display a reduced propensity towards self-association. Clinical evaluations have shown that these so called "monomeric" analogs better mimic the meal-stimulated pharmacokinetics of insulin secretion observed in nondiabetics. Two monomeric insulin analog preparations have successfully obtained regulatory approval and are now commercially available. Efforts to produce optimized basal-acting insulin analogs have lagged behind. While some of these analogs have been engineered using recombinant DNA technology, design strategies in many cases exploit physicochemical properties of

  11. Impact of telephonic interviews on persistence and daily adherence to insulin treatment in insulin-naïve type 2 diabetes patients: dropout study

    PubMed Central

    Yavuz, Dilek Gogas; Bilen, Habip; Sancak, Seda; Garip, Tayfun; Hekimsoy, Zeliha; Sahin, Ibrahim; Yilmaz, Murat; Aydin, Hasan; Atmaca, Aysegul; Sert, Murat; Karakaya, Pinar; Arpaci, Dilek; Oguz, Aytekin; Guvener, Nilgun

    2016-01-01

    Objective The objective of this study is to evaluate the impact of sequential telephonic interviews on treatment persistence and daily adherence to insulin injections among insulin-naïve type 2 diabetes patients initiated on different insulin regimens in a 3-month period. Methods A total of 1,456 insulin-naïve patients with type 2 diabetes (mean [standard deviation, SD] age: 56.0 [12.0] years, 49.1% were females) initiated on insulin therapy and consecutively randomized to sequential (n=733) and single (n=723) telephonic interview groups were included. Data on insulin treatment and self-reported blood glucose values were obtained via telephone interview. Logistic regression analysis was performed for factors predicting increased likelihood of persistence and skipping an injection. Results Overall, 76.8% patients (83.2% in sequential vs 70.3% in single interview group, (P<0.001) remained on insulin treatment at the third month. Significantly higher rate for skipping doses was noted in basal bolus than in other regimens (27.0% vs 15.0% for premixed and 15.8% basal insulin, respectively, P<0.0001). Logistic regression analysis revealed sequential telephonic interview (odds ratio [OR], 1.531; 95% confidence interval [CI], 1.093–2.143; P=0.013), higher hemoglobin A1c levels (OR, 1.090; 95% CI, 0.999–1.189; P=0.049), and less negative appraisal of insulin therapy as significant predictors of higher persistence. Basal bolus regimen (OR, 1.583; 95% CI, 1.011–2.479; P=0.045) and higher hemoglobin A1c levels (OR, 1.114; 95% CI, 1.028–1.207; P=0.008) were the significant predictors of increased likelihood of skipping an injection. Conclusion Our findings revealed positive influence of sequential telephonic interview, although including no intervention in treatment, on achieving better treatment persistence in type 2 diabetes patients initiating insulin. PMID:27274207

  12. Lipid signals and insulin resistance.

    PubMed

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

    2013-12-01

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

  13. Lipid signals and insulin resistance.

    PubMed

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

    2013-12-01

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

  14. Slit injection device

    DOEpatents

    Alger, Terry W.; Schlitt, Leland G.; Bradley, Laird P.

    1976-06-15

    A laser cavity electron beam injection device provided with a single elongated slit window for passing a suitably shaped electron beam and means for varying the current density of the injected electron beam.

  15. Deoxycholic Acid Injection

    MedlinePlus

    Deoxycholic acid injection is used to improve the appearance and profile of moderate to severe submental fat ('double chin'; fatty tissue located under the chin). Deoxycholic acid injection is in a class of medications called ...

  16. Aminocaproic Acid Injection

    MedlinePlus

    Aminocaproic acid injection is used to control bleeding that occurs when blood clots are broken down too quickly. This ... the baby is ready to be born). Aminocaproic acid injection is also used to control bleeding in ...

  17. Calcitonin Salmon Injection

    MedlinePlus

    Calcitonin salmon injection is used to treat osteoporosis in postmenopausal women. Osteoporosis is a disease that causes bones to weaken and break more easily. Calcitonin salmon injection is also used to ...

  18. Sodium Ferric Gluconate Injection

    MedlinePlus

    Sodium ferric gluconate injection is used to treat iron-deficiency anemia (a lower than normal number of ... are also receiving the medication epoetin (Epogen, Procrit). Sodium ferric gluconate injection is in a class of ...

  19. Effects of lidocaine injections into the lateral parabrachial nucleus on dipsogenic and pressor response to central angiotensin 2 in rats

    NASA Technical Reports Server (NTRS)

    Menani, Jose Vanderlei; Beltz, Terry G.

    1995-01-01

    This study investigated the effects of bilateral injections of the local anesthetic, lidocaine, into the lateral parabrachial nucleus (LPBN) on the dipsogenic and pressor responses induced by intracerebroventricular (i.c.v.) injection of angiotensin 2 (ANG 2). Centrally injected ANG 2 (50 ng/1 microliter) induced water intake ( IO.2 +/- 0.8 ml/h) and pressor responses (22 +/- 1 mmHg). Prior bilateral injection of 10% lidocaine (200 nl) into the LPBN increased the water intake (14.2 +/- 1.4 ml/h), but did not change the pressor response (17 +/- 1 mmHg) to i.c.v. ANG 2. Lidocaine alone injected into the LPBN also induced a pressor response (23 +/- 3 mmHg). These results showing that bilateral LPBN injection of lidocaine increase water intake induced bv i.c.v. ANG 2 are consistent with electrolytic and neurotoxic lesion studies and suggest that the LPBN is associated with inhibitory mechanisms controlling water intake induced by ANG 2. These results also provide evidence that it is feasible to reversibly anesthetize this brain area to facilitate fluid-related ingestive behavior.

  20. The insulin dilemma in resource-limited countries. A way forward?

    PubMed

    Gill, G V; Yudkin, J S; Keen, H; Beran, D

    2011-01-01

    The International Insulin Foundation (IIF) has developed and validated a needs-assessment instrument called the Rapid Assessment Protocol for Insulin Access (RAPIA) which has been used in seven countries in four continents to analyse the constraints to delivering effective continuing care for people with diabetes. One major contributor to the difficulties in availability of insulin is a failure to use the least costly sources and types of insulin and other effective drugs for diabetes. The purchase of insulins can consume as much as 10% of government expenditure on drugs, this being highly sensitive to the selection of newer analogue insulins as first-choice options, which cost between three and 13 times more than biosynthetic human insulin. Insulin cartridges for use with injection pens further add to costs. Similar considerations apply to most of the newer treatments for people with type 2 diabetes, which may cost up to 40 times more than metformin and sulfonylureas, still considered first-line drugs by European and US guidelines. Both biosynthetic human insulin and the first-line oral hypoglycaemic drugs are available from generic manufacturers. With the present price differentials, there is thus a growing need for countries involved in tendering for sourcing insulin to be provided with the guarantees of Good Manufacturing Practice, quality and bioequivalence, which would come from a WHO Pre-Qualification Scheme as currently exists for a variety of drugs for chronic diseases, both communicable and non-communicable. The IIF has developed a position statement on the provision and choice of diabetes treatments in resource-limited settings which should be applicable wherever consideration of resources is a component of therapeutic decision making. PMID:20835860

  1. Streptozotocin Aggravated Osteopathology and Insulin Induced Osteogenesis Through Co-treatment with Fluoride.

    PubMed

    Yang, Chen; Zhang, Mengmeng; Li, Yagang; Wang, Yan; Mao, Weixian; Gao, Yuan; Xu, Hui

    2015-12-01

    The role of insulin in the mechanism underlying the excessive fluoride that causes skeletal lesion was studied. The in vitro bone marrow stem cells (BMSC) collected from Kunming mice were exposed to varying concentrations of fluoride with or without insulin. The cell viability and early differentiation of BMSC co-treated with fluoride and insulin were measured by using cell counting kit-8 and Gomori modified calcium-cobalt method, respectively. We further investigated the in vivo effects of varying dose of fluoride on rats co-treated with streptozotocin (STZ). Wistar rats were divided into six groups which included normal control, 10 mg fluoride/kg day group, 20 mg fluoride/kg day group, STZ control, STZ+10 mg fluoride/kg day group, and STZ+20 mg fluoride/kg day group. The rats were administered with sodium fluoride (NaF) by gavage with water at doses 10 and 20 mg fluoride/kg day for 2 months. In a period of one month, half of rats in every group were treated with streptozotocin (STZ) once through intraperitoneal injection at 52 mg/kg body weight. The serum glucose, HbA1c, and insulin were determined. Bone mineral content and insulin release were assessed. The results showed insulin combined with fluoride stimulated BMSC cell viability in vitro. The bone mineral content reduced in rats treated with higher dose of fluoride and decreased immensely in rat co-treated with fluoride and STZ. Similarly, a combination treatment of a high dose of fluoride and STZ decreased insulin sensitivity and activity. To sum up, these data indicated fluoride influenced insulin release, activity, and sensitivity. Furthermore, the insulin state in vivo interfered in the osteogenesis in turn and implied there was a close relation between insulin and bone pathogenesis in the mechanism of fluoride toxicity.

  2. Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

    PubMed

    Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

    2015-09-01

    Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen. PMID:25865149

  3. Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

    PubMed

    Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

    2015-09-01

    Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen.

  4. Rich catalytic injection

    DOEpatents

    Veninger, Albert

    2008-12-30

    A gas turbine engine includes a compressor, a rich catalytic injector, a combustor, and a turbine. The rich catalytic injector includes a rich catalytic device, a mixing zone, and an injection assembly. The injection assembly provides an interface between the mixing zone and the combustor. The injection assembly can inject diffusion fuel into the combustor, provides flame aerodynamic stabilization in the combustor, and may include an ignition device.

  5. Alternative Devices for Taking Insulin

    MedlinePlus

    ... the day. Pumps can also give "bolus" doses—one-time larger doses—of insulin at meals and at times when blood glucose is too high based on the programming set by the user. Frequent blood glucose monitoring ...

  6. [The treatment of type-1 diabetics with insulin-induced lipohypertrophy by liposuction].

    PubMed

    Hauner, H; Olbrisch, R R

    1994-03-25

    Extensive areas of lipohypertrophy at the insulin injection sites on both thighs, upper arms and buttocks had developed in a 22-year-old woman with type 1 diabetes. Tissue biopsy showed fat cells of normal size, while the stromal cells in primary culture from the lipohypertrophy tissue demonstrated a greater degree of new fat-cell formation than normal fat tissue, i.e. there was fat-cell hyperplasia. Although the patient avoided these sites for insulin injection during the subsequent 18 months, the amount of excessive fat tissue did not decrease. As the very obvious fat pads distressed the patient, local liposuction was applied without complication at the six affected sites, removing a total of 2,000 ml of fat.-Liposuction is a low-risk curative procedure for removing extensive insulin-induced lipohypertrophic tissue and quickly achieves a cosmetically satisfactory result.

  7. Pregnancy and the long-acting insulin analogue: a case study.

    PubMed

    Caronna, Silvana; Cioni, Federico; Dall'Aglio, Elisabetta; Arsenio, Leone

    2006-04-01

    R.S. is a 22 years old Caucasian woman suffering from obesity, hypertension and Type I Diabetes Mellitus since the age of 6 years. Type I DM treatment includes 3 insulin injections at meal time and one glargine injection at bedtime. The insulin therapy regimen was prolonged during pregnancy and continued after childbirth. Optimal glycemic compensations were monitored throughout the pregnancy using HbA1c variations and other standard controls included in the OBG routine protocols, all within normal values. The pregnancy ended at the 38th week of gestation with a caesarean birth, during which a 3,54 Kg healthy boy with an APGAR of 9 was born. Both the mother and the newborn resulted in perfect health conditions confirming that the possibility of using glargine insulin profiles during pregnancy in selected cases with close monitoring may exist.

  8. Beam injection into RHIC

    SciTech Connect

    Fischer, W.; Hahn, H.; MacKay, W.W.; Satogata, T.; Tsoupas, N.; Zhang, W.

    1997-07-01

    During the RHIC sextant test in January 1997 beam was injected into a sixth of one of the rings for the first time. The authors describe the injection zone and its bottlenecks. They report on the commissioning of the injection system, on beam based measurements of the kickers and the application program to steer the beam.

  9. Gene Therapy for Diabetes Mellitus in Rats by Hepatic Expression of Insulin

    NASA Astrophysics Data System (ADS)

    Kolodka, Tadeusz M.; Finegold, Milton; Moss, Larry; Woo, Savio L. C.

    1995-04-01

    Type 1 diabetes mellitus is caused by severe insulin deficiency secondary to the autoimmune destruction of pancreatic β cells. Patients need to be controlled by periodic insulin injections to prevent the development of ketoacidosis, which can be fatal. Sustained, low-level expression of the rat insulin 1 gene from the liver of severely diabetic rats was achieved by in vivo administration of a recombinant retroviral vector. Ketoacidosis was prevented and the treated animals exhibited normoglycemia during a 24-hr fast, with no evidence of hypoglycemia. Histopathological examination of the liver in the treated animals showed no apparent abnormalities. Thus, the liver is an excellent target organ for ectopic expression of the insulin gene as a potential treatment modality for type 1 diabetes mellitus by gene therapy.

  10. A Comparison of Glide Force Characteristics Between 2 Prefilled Insulin Lispro Pens

    PubMed Central

    Lennartz, Amanda H.; Ignaut, Debra A.

    2015-01-01

    Background: Glide force, average glide force, and glide force variability of the insulin lispro 200 units/mL pen (Eli Lilly and Company, Indianapolis, IN, USA) were compared to the Humalog® KwikPen® 100 units/mL pen (hereafter, KwikPen; Eli Lilly and Company, Indianapolis, IN, USA). Methods: Data were collected on 2 doses, 2 injection speeds, and 2 needle types. Results: Insulin lispro 200 units/mL pen showed significantly lower maximum glide force, average glide force, and glide force variability than the KwikPen across all combinations of dose size, dose speed, and needle type. Conclusions: The lower glide force observed with the insulin lispro 200 units/mL pen offers another treatment option for patients with type 1 or type 2 diabetes who require greater than 20 units of mealtime insulin daily. PMID:25591858

  11. Bio-Inspired Synthetic Nanovesicles for Glucose-Responsive Release of Insulin

    PubMed Central

    2015-01-01

    A new glucose-responsive formulation for self-regulated insulin delivery was constructed by packing insulin, glucose-specific enzymes into pH-sensitive polymersome-based nanovesicles assembled by a diblock copolymer. Glucose can passively transport across the bilayer membrane of the nanovesicle and be oxidized into gluconic acid by glucose oxidase, thereby causing a decrease in local pH. The acidic microenvironment causes the hydrolysis of the pH sensitive nanovesicle that in turn triggers the release of insulin in a glucose responsive fashion. In vitro studies validated that the release of insulin from nanovesicle was effectively correlated with the external glucose concentration. In vivo experiments, in which diabetic mice were subcutaneously administered with the nanovesicles, demonstrate that a single injection of the developed nanovesicle facilitated stabilization of the blood glucose levels in the normoglycemic state (<200 mg/dL) for up to 5 days. PMID:25268758

  12. Cardiovascular effects of basal insulins.

    PubMed

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  13. Cardiovascular effects of basal insulins

    PubMed Central

    Mannucci, Edoardo; Giannini, Stefano; Dicembrini, Ilaria

    2015-01-01

    Basal insulin is an important component of treatment for both type 1 and type 2 diabetes. One of the principal aims of treatment in patients with diabetes is the prevention of diabetic complications, including cardiovascular disease. There is some evidence, although controversial, that attainment of good glycemic control reduces long-term cardiovascular risk in both type 1 and type 2 diabetes. The aim of this review is to provide an overview of the potential cardiovascular safety of the different available preparations of basal insulin. Current basal insulin (neutral protamine Hagedorn [NPH], or isophane) and basal insulin analogs (glargine, detemir, and the more recent degludec) differ essentially by various measures of pharmacokinetic and pharmacodynamic effects in the bloodstream, presence and persistence of peak action, and within-subject variability in the glucose-lowering response. The currently available data show that basal insulin analogs have a lower risk of hypoglycemia than NPH human insulin, in both type 1 and type 2 diabetes, then excluding additional harmful effects on the cardiovascular system mediated by activation of the adrenergic system. Given that no biological rationale for a possible difference in cardiovascular effect of basal insulins has been proposed so far, available meta-analyses of publicly disclosed randomized controlled trials do not show any signal of increased risk of major cardiovascular events between the different basal insulin analogs. However, the number of available cardiovascular events in these trials is very small, preventing any clear-cut conclusion. The results of an ongoing clinical trial comparing glargine and degludec with regard to cardiovascular safety will provide definitive evidence. PMID:26203281

  14. Biosimilar insulins: a European perspective

    PubMed Central

    DeVries, J H; Gough, S C L; Kiljanski, J; Heinemann, L

    2015-01-01

    Biosimilar insulins are likely to enter clinical practice in Europe in the near future. It is important that clinicians are familiar with and understand the concept of biosimilarity and how a biosimilar drug may differ from its reference product. The present article provides an overview of biosimilars, the European regulatory requirements for biosimilars and safety issues. It also summarizes the current biosimilars approved in Europe and the key clinical issues associated with the use of biosimilar insulins. PMID:25376600

  15. Enhanced insulin binding to blood-brain barrier in vivo and to brain microvessels in vitro in newborn rabbits

    SciTech Connect

    Frank, H.J.; Jankovic-Vokes, T.; Pardridge, W.M.; Morris, W.L.

    1985-08-01

    Insulin is a known growth factor in nonneural tissue, and recent studies have shown that there are insulin receptors throughout the adult and fetal central nervous system. Since insulin has only limited access to the adult brain, this study was undertaken to determine if insulin has increased availability to the newborn brain where it may act as a neonatal brain growth promoter. In vivo brain uptake of SVI-insulin after a single-pass carotid injection was measured in newborn, 3-wk-old and 11-wk-old (adult) rabbits. The brain uptake index (BUI) relative to a THOH reference was 22.0 +/- 1.1% (mean +/- SEM) for newborn, 12.8 +/- 0.6% for 3-wk-old, and 6.5 +/- 0.1% for adults. Specific SVI-insulin binding to isolated cerebral microvessels was similarly increased in the newborn compared with the 3-wk-old and adult animals. Scatchard analysis revealed that the difference was due to an increase in receptor number with only minimal changes in the affinity. The increased availability of circulating insulin to the newborn brain was further corroborated by elevated CSF/serum and brain/serum insulin ratios in the newborn versus adult. These results suggest that insulin has increased access to the newborn brain where it may function as a growth factor.

  16. Graded occlusion of perfused rat muscle vasculature decreases insulin action.

    PubMed

    Vollus, Georgie C; Bradley, Eloise A; Roberts, Merren K; Newman, John M B; Richards, Stephen M; Rattigan, Stephen; Barrett, Eugene J; Clark, Michael G

    2007-04-01

    Insulin increases capillary recruitment in vivo and impairment of this may contribute to muscle insulin resistance by limiting either insulin or glucose delivery. In the present study, the effect of progressively decreased rat muscle perfusion on insulin action using graded occlusion with MS (microspheres; 15 mum in diameter) was examined. EC (energy charge), PCr/Cr (phosphocreatine/creatine ratio), AMPK (AMP-activated protein kinase) phosphorylation on Thr(172) (P-AMPKalpha/total AMPK), oxygen uptake, nutritive capacity, 2-deoxyglucose uptake, Akt phosphorylation on Ser(473) (P-Akt/total Akt) and muscle 2-deoxyglucose uptake were determined. Arterial injection of MS (0, 9, 15 and 30 x 10(6) MS/15 g of hindlimb muscle, as a bolus) into the pump-perfused (0.5 ml x min(-1) x g(-1) of wet weight) rat hindlimb led to increased pressure (-0.5+/-0.8, 15.9+/-2.1, 28.7+/-4.6 and 60.3+/-9.4 mmHg respectively) with minimal changes in oxygen uptake. Nutritive capacity was decreased from 10.6+/-1.0 to 3.8+/-0.9 micromol x g(-1) of muscle x h(-1) (P<0.05) with 30 x 10(6) MS. EC was unchanged, but PCr/Cr was decreased dose-dependently to 61% of basal with 30 x 10(6) MS. Insulin-mediated increases in P-Akt/total Akt decreased from 2.15+/-0.35 to 1.41+/-0.23 (P<0.05) and muscle 2-deoxyglucose uptake decreased from 130+/-19 to 80+/-12 microg x min(-1) x g(-1) of dry weight (P<0.05) with 15 x 10(6) MS; basal P-AMPKalpha in the absence of insulin was increased, but basal P-Akt/total Akt and muscle 2-deoxyglucose uptake were unaffected. In conclusion, partial occlusion of the hindlimb muscle has no effect on basal glucose uptake and marginally impacts on oxygen uptake, but markedly impairs insulin delivery to muscle and, thus, insulin-mediated Akt phosphorylation and glucose uptake.

  17. Relapsing insulin-induced lipoatrophy, cured by prolonged low-dose oral prednisone: a case report

    PubMed Central

    2011-01-01

    Introduction Circumscript, progressing lipoatrophy at the insulin injection sites is an unexplained, however rare condition in diabetes mellitus. Case presentation We report a case of severe localised lipoatrophy developing during insulin pump-treatment (continuous subcutaneous insulin infusion) with the insulin analogue lispro (Humalog®) in a woman with type-1 diabetes mellitus. After 11 months of progressing lipoatrophy at two spots on the abdomen, low-dose prednisone (5-10 mg) p.o. was given at breakfast for 8 months, whereby the atrophic lesions centripetally re-filled with subcutaneous fat tissue (confirmed by MRI) despite ongoing use of insulin lispro. However, 4 weeks after cessation of prednisone, lipoatrophy relapsed, but resolved after another 2 months of low-dose prednisone. No further relapse was noted during 12 months of follow-up on insulin-pump therapy with Humalog®. Conclusion Consistent with an assumed inflammatory nature of the condition, low-dose oral prednisone appeared to have cured the lipoatrophic reaction in our patient. Our observation suggests a temporary intolerance of the subcutaneous fat tissue to insulin lispro (Humalog®), triggered by an unknown endogenous mechanism. PMID:22145998

  18. Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion

    PubMed Central

    Wang, Fei; Kohan, Alison B.; Kindel, Tammy L.; Corbin, Kathryn L.; Nunemaker, Craig S.; Obici, Silvana; Woods, Stephen C.; Davidson, W. Sean; Tso, Patrick

    2012-01-01

    Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine in response to fat absorption. Here we demonstrate a potential role for apoA-IV in regulating glucose homeostasis. ApoA-IV–treated isolated pancreatic islets had enhanced insulin secretion under conditions of high glucose but not of low glucose, suggesting a direct effect of apoA-IV to enhance glucose-stimulated insulin release. This enhancement involves cAMP at a level distal to Ca2+ influx into the β cells. Knockout of apoA-IV results in compromised insulin secretion and impaired glucose tolerance compared with WT mice. Challenging apoA-IV−/− mice with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in WT mice. Administration of exogenous apoA-IV to apoA-IV−/− mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet. Finally, we demonstrate that exogenous apoA-IV injection decreases blood glucose levels and stimulates a transient increase in insulin secretion in KKAy diabetic mice. These results suggest that apoA-IV may provide a therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes. PMID:22619326

  19. Insulin glargine in type 2 diabetes in everyday clinical practice: 7 years experience.

    PubMed

    Schreiber, S A

    2008-07-01

    Insulin therapy is often essential in people with type 2 diabetes mellitus (T2DM) but is typically not initiated early enough or aggressive enough, leading to worsening of glycaemic control and the majority of people staying above recommended haemoglobin A(1c) (HbA(1c)) targets of <7%. The extensive clinical experience gained with insulin glargine, in particular, the low risk of hypoglycaemia and consistent improvements in HbA(1c), suggests that insulin glargine can be initiated aggressively to help patients reach such HbA(1c) targets. However, many clinicians may be unaware of how easy it is to initiate insulin glargine. Indeed, the once-daily injection of insulin glargine plus once-daily measurement of blood glucose should provide little difficulty for patients. In the current review, the options for the initiation of insulin glargine in T2DM and how the patient can become more involved in management of their diabetes are discussed. The advantages of insulin glargine in randomized controlled trials and how these have translated into everyday clinical practice are also discussed.

  20. Berberine in Combination with Insulin Has Additive Effects on Titanium Implants Osseointegration in Diabetes Mellitus Rats

    PubMed Central

    Lu, Li; Zhijian, Huang; Lei, Li; Wenchuan, Chen; Zhimin, Zhu

    2015-01-01

    This study evaluated the effects of berberine in combination with insulin on early osseointegration of implants in diabetic rats. Fifty male Sprague-Dawley rats were randomly divided into 5 groups: healthy rats were used as control (HC), and streptozotocin-induced diabetic rats were treated with insulin, berberine, berberine + insulin (IB), or no treatment. Each rat received one machined-surface cp-Ti implant into the right tibia and was given insulin injection and/or gavage feeding with berberine daily for 8 weeks until being sacrificed. Serum levels of alkaline phosphatase (ALP) and bone gamma-carboxyglutamic acid-containing protein (BGP) were analyzed in each group. Peri-implant mineral apposition was marked by fluorochrome double-labeling and osseointegration was histomorphologically examined. The ALP and BGP levels decreased in diabetic rats but were successfully corrected by insulin and berberine combined treatment. Moreover, untreated diabetic rats had less labeled mineral apposition and impaired osseointegration. In contrast, Groups I, B, and IB were observed with increased peri-implant bone formation. The combination treatment of insulin and berberine was more effective than each administrated as a monotherapy. These results suggest that berberine combined with insulin could promote osseointegration in diabetic rats, thereby highlighting its potential application to patients, though further studies are needed. PMID:26783411