Hørsholm, Denmark
Hørsholm, Denmark

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Vrang N.,Gubra ApS | Grove K.,Oregon Health And Science University
Brain Research | Year: 2011

The nucleus of the solitary tract (NTS) contains a small population of neurons expressing preproglucagon. In these neurons preproglucagon is processed to the glucagon-like-peptides 1 and 2 (GLP-1 and GLP-2) and oxyntomodulin. Whereas the neuroanatomy of these neurons is well characterized in rodents the location and projection of preproglucagon neurons have never been described in primates. The purpose of the present study was to characterize the location of preproglucagon neurons and their projections in the non-human primate using radioactive in situ hybridization and immunohistochemistry. In situ hybridization revealed preproglucagon mRNA expressing neurons in the caudal nucleus of the solitary tract extending laterally through the intermediate reticular nucleus into the A1 area. Using an antibody raised against rat GLP-2, GLP-2-immunoreactive (- ir) cell bodies were found in the same areas as the preproglucagon mRNA. Only very few GLP-2-ir nerve fibers were observed in the caudal brainstem and mostly in the same areas as the GLP-2-ir cell bodies. The most prominent GLP-2-ir terminal fields were detected in the hypothalamus and rostrally in the bed nucleus of the stria terminalis complex. In the hypothalamus, GLP-2-ir fibers arborized extensively in the paraventricular nucleus of the hypothalamus (PVN), the dorsomedial hypothalamic nucleus (DMH) and the arcuate nucleus (Arc), the latter containing the densest fiber-plexus. The findings indicate that the brainstem preproglucagon neuronal system is highly conserved between rat and non-human primate with the exception of a much denser innervation of the mediobasal hypothalamus in the primate brain. © 2011 Elsevier B.V.


Jelsing J.,Gubra ApS | Vrang N.,Gubra ApS | Hansen G.,Gubra ApS | Raun K.,NovoNordisk A S | And 2 more authors.
Diabetes, Obesity and Metabolism | Year: 2012

Aim: Previous studies with the novel once daily glucagon-like peptide-1 (GLP-1) analogue liraglutide and the GLP-1 receptor agonist exenatide have revealed profound insulinotrophic and antidiabetic effects, but also potent effects on gastric emptying (GE) and long-term and lasting reductions in body weight. In this study, we examined the acute and chronic effects of two different GLP-1 analogues with different pharmacokinetic profiles on GE, food intake and body weight. Methods: On the basis of a series of dose-finding studies, the doses of exenatide and liraglutide with similar acute anorectic effects were identified. GE was assessed using a standard acetaminophen release assay. After the acute test, rats were dosed bi-daily for 14 days in which period food intake and body weight was monitored. On day 14, the GE rate was reassessed. Results: While both compounds exerted robust acute reductions in GE, the effect was markedly diminished following 14 days of dosing with liraglutide. In contrast, exenatide-treated rats still displayed a profound reduction in GE at the 14-day time-point. Both compounds exerted similar effects on body weight. Conclusion: The data suggest that the 'gastric inhibitory' GLP-1 receptors in rats are subject to desensitization/tachyphylaxis but that this effect is dependent on full 24-h exposure as obtained by liraglutide. The body weight-lowering effects of GLP-1 receptor stimulation are not subject to desensitization. These data indicate that regulation of appetite signals in the brain, and not GE, is the main mechanism for liraglutide-induced weight loss. © 2012 Blackwell Publishing Ltd.


Vrang N.,Gubra ApS | Jelsing J.,Gubra ApS | Simonsen L.,Novo Nordisk AS | Jensen A.E.,Gubra ApS | And 3 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012

A possible association between glucagon-like peptide-1 (GLP-1) analogs and incidences of pancreatitis has been suggested based on clinical studies. In male and female diabetic Zucker diabetic fatty (ZDF) rats, we investigated the effects of continuous administration of liraglutide and exenatide on biochemical [lipase, pancreatic amylase (P-amylase)] and histopathological markers of pancreatitis. Male and female ZDF rats were dosed for 13 wk with liraglutide (0.4 or 1.0 mg·kg -1·day -1 sc once daily) or exenatide (0.25 mg·kg -1·day -1 sc, Alzet osmotic minipumps). P-amylase and lipase plasma activity were measured, and an extended histopathological and stereological (specific cell mass and proliferation rate) evaluation of the exocrine and the endocrine pancreas was performed. Expectedly, liraglutide and exenatide lowered blood glucose and Hb A 1c in male and female ZDF rats, whereas β-cell mass and proliferation rate were increased with greatly improved blood glucose control. Whereas neither analog affected lipase activity, small increases in P-amylase activity were observed in animals treated with liraglutide and exenatide. However, concurrent or permanent increases in lipase and P-amylase activity were never observed. Triglycerides were lowered by both GLP-1 analogs. The qualitative histopathological findings did not reveal adverse effects of liraglutide. The findings were mainly minimal in severity and focal in distribution. Similarly, the quantitative stereological analyses revealed no effects of liraglutide or exenatide on overall pancreas weight or exocrine and duct cell mass or proliferation. The present study demonstrates that, in overtly diabetic male and female ZDF rats, prolonged exposure to GLP-1 receptor agonists does not affect biochemical or histopathological markers of pancreatitis, and whereas both exenatide and liraglutide increase β-cell mass, they have no effect on the exocrine pancreas. However, clinical outcome studies and studies using primate tissues and/or studies in nonhuman primates are needed to further assess human risk. © 2012 the American Physiological Society.


Dalboge L.S.,Gubra ApS | Almholt D.L.C.,Zealand Pharma A S | Neerup T.S.R.,Zealand Pharma A S | Vrang N.,Gubra ApS | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014

Antidiabetic treatments aiming to preserve or even to increase β-cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist ZP3022 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN-8Ado-8Ado-YGWLDF-NH2) on glycemic control, β-cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks, with terminal assessment of hemoglobin A1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of β-cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in β-cell mass after 4 and 8 weeks of treatment, whereas the effect of liraglutide was transient. The expansion in β-cell mass observed in the ZP3022-treated mice appeared to be driven by increased β-cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased but the number of islets remained constant. Our data demonstrate that the GLP-1-gastrin dual agonist ZP3022 causes a sustained improvement in glycemic control accompanied by an increase in β-cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases β-cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of antidiabetic treatments. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Hansen G.,Gubra Aps | Jelsing J.,Gubra Aps | Vrang N.,Gubra Aps
Acta Pharmacologica Sinica | Year: 2012

Aim:To validate the gubra DIO-rats as a useful animal model of human obesity.Methods:The gubra diet-induced obesity (DIO) rat model was based on male Sprague-Dawley rats with ad libitum access to regular chow and a palatable diet rich in fat and sugar. To evaluate the versatility of the gubra DIO-rats as a valid model of human obesity syndrome, the efficacy of 2 weight loss compounds liraglutide and sibutramine with different mechanisms of action were examined in 7-month-old gubra DIO-rats. Liraglutide (200 μg/kg, sc) was administered bi-daily, and sibutramine (5 mg/kg, po) was administered once daily for 23 d.Results:Both the compounds effectively reduced the food intake, body weight and total fat mass as measured by nuclear magnetic resonance. Whereas the 5-HT reuptake inhibitor/5-HT receptor agonist sibutramine reduced the intake of both chow and the gubra-diet, the GLP-1 analogue liraglutide predominantly reduced the intake of the highly palatable diet, indicating a shift in food preference. Sibutramine lowered the insulin sensitivity index, primarily via reductions in glucose-stimulated insulin secretion.Conclusion:This animal model responds well to 2 weight loss compounds with different mechanisms of action. Moreover, the gubra DIO-rat can be particularly useful for the testing of compounds with potential effects on diet preference. © 2012 CPS and SIMM All rights reserved.


Vrang N.,Gubra ApS | Larsen P.J.,Eli Lilly and Company
Progress in Neurobiology | Year: 2010

The scientific understanding of preproglucagon derived peptides has provided people with type 2 diabetes with two novel classes of glucose lowering agents, the dipeptidyl peptidase IV (DPP-IV) inhibitors and GLP-1 receptor agonists. For the scientists, the novel GLP-1 agonists, and DPP-IV inhibitors have evolved as useful tools to understand the role of the preproglucagon derived peptides in normal physiology and disease. However, the overwhelming interest attracted by GLP-1 analogues as potent incretins has somewhat clouded the efforts to understand the importance of preproglucagon derived peptides in other physiological contexts. In particular, our neurobiological understanding of the preproglucagon expressing neuronal pathways in the central nervous system as well as the degree to which central GLP-1 receptors are targeted by peripherally administered GLP-1 receptor agonists is still fairly limited. The role of GLP-1 as an anorectic neurotransmitter is well recognized, but clarification of the neuronal targets and physiological basis of this response is further warranted, as is the mapping of GLP-1 sensitive neurons involved in a variety of neuroendocrine and behavioral responses. Further recent evidence points to GLP-1 as a central neuropeptide with neuroprotective capabilities potentially mitigating a wide array of neurodegenerative conditions. It is the aim of the present review to summarize our current understanding of preproglucagon derived peptides as neurotransmitters in the central nervous system. © 2010 Elsevier Ltd.


Hansen C.F.,Gubra Aps | Hansen C.F.,Copenhagen University | Vrang N.,Gubra Aps | Torp Sangild P.,Copenhagen University | Jelsing J.,Gubra Aps
American Journal of Translational Research | Year: 2013

Background: Gut secreted incretin hormones and gastric bypass surgery currently provides some of the most successful treatments for diabetes and obesity respectively. However, despite the evident importance of the gut endocrine system no information exists on the total number and distribution of different types of endocrine cells in the gut. Here we have used the established preclinical Zucker Diabetic Fatty (ZDF) rat model which displays elevated levels of GLP-1 to assess L-cell distribution and L-cell dynamics in the full rostro-caudal extension of the rat intestinal tract. Methods: Using mathematically unbiased stereology we provide total and regional estimates of gut volume, gut surface area and the total number of L-cells throughout the intestinal tract in obese ZDF rats and lean controls. Results: The total number of L-cells in the lean and obese ZDF gut is estimated to 4.8 and 10.9 million, respectively, coupled with a corresponding near doubling in total gut volume and total surface area. L-cell numbers were found to be distributed rather evenly throughout the jejunum, ileum and colon. Conclusion: The present study provides the first stereological report of total L-cell number and L-cell distribution throughout the rat intestinal tract. In contrast to the currently held view, the majority of L-cells are actually located proximal to the traditionally defined ileum and colon.


The present invention relates to neuromedin U receptor agonist peptides comprising at least one serum albumin binding amino acid residue, said serum albumin binding amino acid residue being distanced by at least one but less than 16 amino acids from the part of the peptide comprising the active site responsible for NMU receptor binding, as well as to pharmaceutical and veterinary compositions comprising the peptides.


The present invention relate to molecular building blocks of the formula R_(1)-A-R_(3), wherein A is a carbohydrate derivative and R_(1) is hydrogen or an amino protecting group and R_(3) is either a hydroxyl, a protecting group or a leaving group. The building blocks are capable of attaching carbohydrate derivatives and fatty acid residues to amino acids. By use of these carbohydrate building blocks, means for providing proteins and peptides with the additional functionalities of carbohydrates and of fatty acid residues and particularly to provide peptides and proteins with the combined functionalities of fatty acids and carbohydrates are provided.


Jelsing J.,Gubra ApS | Vrang N.,Gubra ApS | van Witteloostuijn S.B.,Gubra ApS | Mark M.,Boehringer Ingelheim | Klein T.,Boehringer Ingelheim
Journal of Endocrinology | Year: 2012

Recent data indicate that dipeptidyl peptidase 4 (DPP4) inhibitors have anti-inflammatory and β-cell-sparing effects in animal models of type 1 diabetes. To evaluate the effects of the DPP4 inhibitor linagliptin on β-cell mass and insulinitis, we examined the progression of diabetes (blood glucose >11 mmol/l) in non-obese diabetic (NOD) mice with terminal stereological assessment of cellular pancreatic changes. Female NOD mice were fed a normal chow diet or a diet containing linagliptin 0.083 g/kg chow for 60 days. At study end, the incidence of diabetes in linagliptin-treated mice was reduced by almost 50% compared with vehicle (10 of 31 mice vs 18 of 30 mice, P=0.021). The total islet mass and total β-cell mass, identified by insulin immunoreactivity, were greater in non-diabetic linagliptin-treated mice compared with nondiabetic vehicle-treated mice (P<0.01 for both) but were greatly reduced in diabetic mice irrespective of treatment. No changes were seen in the a, d and g endocrine cell pool. Moreover, the total mass of lymphocyte insulinitis was significantly reduced in linagliptin-treated mice compared with vehicle. The data indicate that linagliptin treatment delays the onset of diabetes in NOD mice by protecting β-cell mass. © 2012 Society for Endocrinology.

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