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  • 1
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    Online Resource
    Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 298, No. 1 ( 2010-01), p. R43-R50
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 298, No. 1 ( 2010-01), p. R43-R50
    Abstract: Insulin detemir is a novel human insulin analog that does not show the usual propensity for weight gain in diabetic patients. We speculated that this beneficial effect could be due to insulin detemir exerting stronger anorectic effects within the brain than other insulins. To study the central effects of regular human insulin and insulin detemir on food intake, the present study was undertaken. We used acute intracerebroventricular insulin injections to compare food intake and body weight in rats fed ad libitum. Contrary to previously published data, we found that neither regular human insulin (8 or 32 mU) nor insulin detemir (1,290 pmol) reduced food intake in this model. Melanotan-II was also injected intracerebroventricularly as a positive control, and significantly reduced food intake and body weight, suggesting that our intracerebroventricular model is able to show anorectic effects. A series of experiments was therefore conducted in which different set-ups were tested to investigate which factors would be required to produce the reported anorectic effect of intracerebroventricular insulin. Although we varied rat strain, stereotactic coordinates, formulations of insulin and vehicle, dose, volume, and time of injection, the anorectic effect of intracerebroventricular insulin could not be replicated. Therefore, we suggest that acute intracerebroventricularly injected insulin does not robustly inhibit food intake in rats. Based on our results, the acute intracerebroventricular injection procedure may not be a preferred method for studying the central anorectic effects of insulin in rats. Instead, administrations over time or locally in hypothalamic nuclei might be recommended.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.90736.2008
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477297-8
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  • 2
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    A Novel Strategy to Prevent Advanced Atherosclerosis and Lower Blood Glucose in a Mouse Model of Metabolic Syndrome
    American Diabetes Association ; 2018
    In:  Diabetes Vol. 67, No. 5 ( 2018-05-01), p. 946-959
    Details
    In: Diabetes, American Diabetes Association, Vol. 67, No. 5 ( 2018-05-01), p. 946-959
    Abstract: Cardiovascular disease caused by atherosclerosis is the leading cause of mortality associated with type 2 diabetes and metabolic syndrome. Insulin therapy is often needed to improve glycemic control, but it does not clearly prevent atherosclerosis. Upon binding to the insulin receptor (IR), insulin activates distinct arms of downstream signaling. The IR-Akt arm is associated with blood glucose lowering and beneficial effects, whereas the IR-Erk arm might exert less desirable effects. We investigated whether selective activation of the IR-Akt arm, leaving the IR-Erk arm largely inactive, would result in protection from atherosclerosis in a mouse model of metabolic syndrome. The insulin mimetic peptide S597 lowered blood glucose and activated Akt in insulin target tissues, mimicking insulin’s effects, but only weakly activated Erk and even prevented insulin-induced Erk activation. Strikingly, S597 retarded atherosclerotic lesion progression through a process associated with protection from leukocytosis, thereby reducing lesional accumulation of inflammatory Ly6Chi monocytes. S597-mediated protection from leukocytosis was accompanied by reduced numbers of the earliest bone marrow hematopoietic stem cells and reduced IR-Erk activity in hematopoietic stem cells. This study provides a conceptually novel treatment strategy for advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db17-0744
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2018
    detail.hit.zdb_id: 1501252-9
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  • 3
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    Characterization of 1,4‐dideoxy‐1,4‐imino‐ d ‐arabinitol (DAB) as an inhibitor of brain glycogen shunt activity
    Wiley ; 2008
    In:  Journal of Neurochemistry Vol. 105, No. 4 ( 2008-05), p. 1462-1470
    Details
    In: Journal of Neurochemistry, Wiley, Vol. 105, No. 4 ( 2008-05), p. 1462-1470
    Abstract: The pharmacological properties of 1,4‐dideoxy‐1,4‐imino‐ d ‐arabinitol (DAB), a potent inhibitor of glycogen phosphorylase and synthase activity in liver preparations, were characterized in different brain tissue preparations as a prerequisite for using it as a tool to investigate brain glycogen metabolism. Its inhibitory effect on glycogen phosphorylase was studied in homogenates of brain tissue and astrocytes and IC 50 ‐values close to 400 nM were found. However, the concentration of DAB needed for inhibition of glycogen shunt activity, i.e. glucose metabolism via glycogen, in intact astrocytes was almost three orders of magnitude higher. Additionally, such complete inhibition required a pre‐incubation period, a finding possibly reflecting a limited permeability of the astrocytic membrane. DAB did not affect the accumulation of 2‐deoxyglucose‐6‐phosphate indicating that the transport of DAB is not mediated by the glucose transporter. DAB had no effect on enzymes involving glucose‐6‐phosphate, i.e. glucose‐6‐phosphate dehydrogenase, phosphoglucoisomerase and hexokinase. Furthermore, DAB was evaluated in a functional preparation of the isolated mouse optic nerve, in which its presence severely reduced the ability to sustain evoked compound action potentials in the absence of glucose, a condition in which glycogen serves as an important energy substrate. Based on the experimental findings, DAB can be used to evaluate glycogen shunt activity and its functional importance in intact brain tissue and cells at a concentration of 300–1000 μM and a pre‐incubation period of 1 h.
    Type of Medium: Online Resource
    ISSN: 0022-3042 , 1471-4159
    URL: Issue
    URL: Article
    DOI: 10.1111/jnc.2008.105.issue-4
    DOI: 10.1111/j.1471-4159.2008.05250.x
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 2020528-4
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  • 4
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    Functional significance of brain glycogen in sustaining glutamatergic neurotransmission
    Wiley ; 2009
    In:  Journal of Neurochemistry Vol. 109, No. s1 ( 2009-05), p. 80-86
    Details
    In: Journal of Neurochemistry, Wiley, Vol. 109, No. s1 ( 2009-05), p. 80-86
    Abstract: The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co‐cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue d ‐[ 3 H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co‐cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d ‐lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d ‐lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.
    Type of Medium: Online Resource
    ISSN: 0022-3042 , 1471-4159
    URL: Issue
    URL: Article
    DOI: 10.1111/jnc.2009.109.issue-s1
    DOI: 10.1111/j.1471-4159.2009.05915.x
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 2020528-4
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  • 5
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    Online Resource
    Dual treatment with a fixed ratio of glucagon and insulin increases the therapeutic window of insulin in diabetic rats
    Wiley ; 2018
    In:  Physiological Reports Vol. 6, No. 6 ( 2018-03), p. e13657-
    Details
    In: Physiological Reports, Wiley, Vol. 6, No. 6 ( 2018-03), p. e13657-
    Type of Medium: Online Resource
    ISSN: 2051-817X
    URL: Article
    DOI: 10.14814/phy2.13657
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2724325-4
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  • 6
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    Noradrenergic and GABAergic systems in the medial hypothalamus are activated during hypoglycemia
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 280, No. 2 ( 2001-02-01), p. R563-R569
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 280, No. 2 ( 2001-02-01), p. R563-R569
    Abstract: Noradrenergic and GABAergic systems in the medial hypothalamus influence plasma glucose and may be activated during glucoprivation. Microdialysis probes were placed into the ventromedial nucleus (VMH), lateral hypothalamus (LHA), and paraventricular nucleus (PVH) of male Sprague-Dawley rats to monitor extracellular concentrations of norepinephrine (NE) and GABA. During systemic hypoglycemia, induced by insulin (1.0 U/kg), NE concentrations increased in the VMH ( P 〈 0.05) and PVH ( P = 0.06) in a bimodal fashion during the first 10 min and 20–30 min after insulin administration. In the VMH, GABA concentrations increased ( P 〈 0.05) in a similar manner as NE. Extracellular NE concentrations in the LHA were slightly lower ( P = 0.13), and GABA levels remained at baseline. The increases in NE and GABA in the VMH were absent during euglycemic clamp; however, NE in the PVH still increased, reflecting a direct response to hyperinsulinemia. On the basis of these data, we propose that the activity of noradrenergic afferents to the medial hypothalamus is increased during hypoglycemia and influences the activity of local GABAergic systems to activate appropriate physiological compensatory mechanisms.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.2001.280.2.R563
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477297-8
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  • 7
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    Preclinical exploration of combined glucagon inhibition and liver-preferential insulin for treatment of diabetes using in vitro assays and rat and mouse models
    Springer Science and Business Media LLC ; 2023
    In:  Diabetologia Vol. 66, No. 2 ( 2023-02), p. 376-389
    Details
    In: Diabetologia, Springer Science and Business Media LLC, Vol. 66, No. 2 ( 2023-02), p. 376-389
    Abstract: Normalisation of blood glucose in individuals with diabetes is recommended to reduce development of diabetic complications. However, risk of severe hypoglycaemia with intensive insulin therapy is a major obstacle that prevents many individuals with diabetes from obtaining the recommended reduction in HbA 1c . Inhibition of glucagon receptor signalling and liver-preferential insulin action have been shown individually to have beneficial effects in preclinical models and individuals with diabetes (i.e. improved glycaemic control), but also have effects that are potential safety risks (i.e. alpha cell hyperplasia in response to glucagon receptor antagonists and increased levels of liver triacylglycerols and plasma alanine aminotransferase activity in response to glucagon receptor antagonists and liver-preferential insulin). We hypothesised that a combination of glucagon inhibition and liver-preferential insulin action in a dual-acting molecule would widen the therapeutic window. By correcting two pathogenic mechanisms (dysregulated glucagon signalling and non-physiological distribution of conventional insulin administered s.c.), we hypothesised that lower doses of each component would be required to obtain sufficient reduction of hyperglycaemia, and that the undesirable effects that have previously been observed for monotreatment with glucagon antagonists and liver-preferential insulin could be avoided. Methods A dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule was designed and tested in rodent models (normal rats, rats with streptozotocin-induced hyperglycaemia, db / db mice and mice with diet-induced obesity and streptozotocin-induced hyperglycaemia), allowing detailed characterisation of the pharmacokinetic and pharmacodynamic properties of the dual-acting molecule and relevant control compounds, as well as exploration of how the dual-acting molecule influenced glucagon-induced recovery and spontaneous recovery from acute hypoglycaemia. Results This molecule normalised blood glucose in diabetic models, and was markedly less prone to induce hypoglycaemia than conventional insulin treatment (approximately 4.6-fold less potent under hypoglycaemic conditions than under normoglycaemic conditions). However, compared to treatment with conventional long-acting insulin, this dual-acting molecule also increased triacylglycerol levels in the liver (approximately 60%), plasma alanine aminotransferase levels (approximately twofold) and alpha cell mass (approximately twofold). Conclusions/interpretation While the dual-acting glucagon receptor inhibitor and liver-preferential insulin molecule showed markedly improved regulation of blood glucose, effects that are potential safety concerns persisted in the pharmacologically relevant dose range. Graphical abstract
    Type of Medium: Online Resource
    ISSN: 0012-186X , 1432-0428
    URL: Article
    DOI: 10.1007/s00125-022-05828-w
    RVK:
    XA 40615
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1458993-X
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  • 8
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    Online Resource
    Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test
    Elsevier BV ; 1996
    In:  European Journal of Pharmacology Vol. 301, No. 1-3 ( 1996-4), p. 19-25
    Details
    In: European Journal of Pharmacology, Elsevier BV, Vol. 301, No. 1-3 ( 1996-4), p. 19-25
    Type of Medium: Online Resource
    ISSN: 0014-2999
    URL: Article
    DOI: 10.1016/0014-2999(96)00064-7
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1996
    detail.hit.zdb_id: 1483526-5
    SSG: 15,3
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  • 9
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    Receptor-isoform-selective insulin analogues give tissue-preferential effects
    Portland Press Ltd. ; 2011
    In:  Biochemical Journal Vol. 440, No. 3 ( 2011-12-15), p. 301-308
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 440, No. 3 ( 2011-12-15), p. 301-308
    Abstract: The relative expression patterns of the two IR (insulin receptor) isoforms, +/− exon 11 (IR-B/IR-A respectively), are tissue-dependent. Therefore we have developed insulin analogues with different binding affinities for the two isoforms to test whether tissue-preferential biological effects can be attained. In rats and mice, IR-B is the most prominent isoform in the liver ( & gt;95%) and fat ( & gt;90%), whereas in muscles IR-A is the dominant isoform ( & gt;95%). As a consequence, the insulin analogue INS-A, which has a higher relative affinity for human IR-A, had a higher relative potency [compared with HI (human insulin)] for glycogen synthesis in rat muscle strips (26%) than for glycogen accumulation in rat hepatocytes (5%) and for lipogenesis in rat adipocytes (4%). In contrast, the INS-B analogue, which has an increased affinity for human IR-B, had higher relative potencies (compared with HI) for inducing glycogen accumulation (75%) and lipogenesis (130%) than for affecting muscle (45%). For the same blood-glucose-lowering effect upon acute intravenous dosing of mice, INS-B gave a significantly higher degree of IR phosphorylation in liver than HI. These in vitro and in vivo results indicate that insulin analogues with IR-isoform-preferential binding affinity are able to elicit tissue-selective biological responses, depending on IR-A/IR-B expression.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20110880
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2011
    detail.hit.zdb_id: 1473095-9
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  • 10
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    Obesity and Type 2 Diabetes in Rats are Associated with Altered Brain Glycogen and Amino-Acid Homeostasis
    SAGE Publications ; 2010
    In:  Journal of Cerebral Blood Flow & Metabolism Vol. 30, No. 8 ( 2010-08), p. 1527-1537
    Details
    In: Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 30, No. 8 ( 2010-08), p. 1527-1537
    Abstract: Obesity and type 2 diabetes have reached epidemic proportions; however, scarce information about how these metabolic syndromes influence brain energy and neurotransmitter homeostasis exist. The objective of this study was to elucidate how brain glycogen and neurotransmitter homeostasis are affected by these conditions. [1- 13 C]glucose was administered to Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats. Sprague–Dawley (SprD), Zucker lean (ZL), and ZDF lean rats were used as controls. Several brain regions were analyzed for glycogen levels along with 13 C-labeling and content of glutamate, glutamine, GABA, aspartate, and alanine. Blood glucose concentrations and 13 C enrichment were determined. 13 C-labeling in glutamate was lower in ZO and ZDF rats in comparison with the controls. The molecular carbon labeling (MCL) ratio between alanine and glutamate was higher in the ZDF rats. The MCL ratios of glutamine and glutamate were decreased in the cerebellum of the ZO and the ZDF rats. Glycogen levels were also lower in this region. These results suggest that the obese and type 2 diabetic models were associated with lower brain glucose metabolism. Glucose metabolism through the TCA cycle was more decreased than glycolytic activity. Furthermore, reduced glutamate–glutamine cycling was also observed in the obese and type 2 diabetic states.
    Type of Medium: Online Resource
    ISSN: 0271-678X , 1559-7016
    URL: Article
    DOI: 10.1038/jcbfm.2010.61
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2010
    detail.hit.zdb_id: 2039456-1
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