Inger Thorup
Novo Nordisk
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Publication
Featured researches published by Inger Thorup.
American Journal of Physiology-endocrinology and Metabolism | 2012
Niels Vrang; Jacob Jelsing; Lotte Simonsen; Andres Eskjær Jensen; Inger Thorup; Henrik Søeborg; Lotte Bjerre Knudsen
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.
Biomarkers | 2005
Frederikke Lihme Egerod; Henriette S. Nielsen; L. Iversen; Inger Thorup; T. Storgaard; M. B. Oleksiewicz
Abstract Small-molecule agonists of the peroxisome proliferator-activated receptor (PPAR) α and γ isoforms (dual-acting PPAR agonists) can cause urothelial cancers in rodents. Rats were dosed orally for 16 days with bladder carcinogenic (ragaglitazar) as well as non-bladder carcinogenic (fenofibrate and rosiglitazone) PPAR agonists and protein changes were assayed in the urinary bladder urothelium by Western blotting. Dose levels reflected 10–20× human exposure, and the ragaglitazar dose was in the carcinogenic range. Ragaglitazar induced expression of the transcription factor Egr-1, phosphorylation of the c-Jun transcription factor and phosphorylation of the ribosomal S6 protein were observed. These changes were also observed in rats dosed with either rosiglitazone or fenofibrate. However, the protein changes were stronger (Egr-1 induction) or of a longer duration (S6 phosphorylation) in ragaglitazar-treated animals. Animals co-administered fenofibrate (a specific PPARα agonist) and rosiglitazone (a specific PPARγ agonist) exhibited Egr-1 and S6 protein changes more similar to those induced by ragaglitazar (a dual-acting PPARα/γ agonist) than either fenofibrate or rosiglitazone alone. The findings suggest that ragaglitazar causes Egr-1, c-Jun and S6 protein changes in the urothelium by a mechanism involving PPARα as well as PPARγ, and that the Egr-1, c-Jun and S6 protein changes might have potential biomarker value.
Toxicologic Pathology | 2005
Martin B. Oleksiewicz; Inger Thorup; Henriette S. Nielsen; Hanne V. Andersen; Anne Charlotte Hegelund; Lars Iversen; Torben S. Guldberg; Peter R. Brinck; Ingrid Sjögren; Ulla K. Thinggaard; Lis Jørgensen; Marianne B. Jensen
Some developmental dual-acting PPARα/γ agonists, such as ragaglitazar, have shown carcinogenic effects in the rodent urinary bladder urothelium after months-years of dosing. We examined early (precancerous) changes in the bladder urothelium of rats orally dosed with ragaglitazar, using a newly developed flow cytometric method. Following 3 weeks of oral ragaglitazar dosing, increases in physical size occurred in a generalized fashion in rat bladder urothelial cells, determined by flow cytometry. Protein/DNA measurements confirmed increased protein content of urothelial cells in the bladder, and hypertrophy was observed in the kidney pelvis urothelium by histopathology. In animals exhibiting urothelial hypertrophy, no cell cycle changes were detected in parallel samples of bladder urothelium. Interestingly, urothelial cells from normal rats were found to constitute a unique type of noncycling population, with high G2/M fractions. In summary, our findings showed that in the urothelium of ragaglitazar-treated animals, hypertrophy (increased size and protein content per cell) was an early change, that affected the whole bladder urothelial cell population. The urothelial hypertrophy was primary, i.e., occurred in the absence of similarly pronounced changes in cell cycle distributions. To our knowledge, this is the first report of a direct hypertrophic effect of a PPAR agonist. Urothelial hypertrophy might be a relevant early biological endpoint in mechanistic studies regarding the bladder-carcinogenic effect of PPAR agonists.
Cancer Letters | 2001
Morten Poulsen; Anne-Marie Mølck; Inger Thorup; Vibeke Breinholt; Otto Meyer
The aim of the present study was to investigate the enhancing effect of dietary sugar on the development of aberrant crypt foci (ACF) in male F344 rats initiated with azoxymethane (AOM). The potential role of sugar as either a co-initiator or a promoter was investigated by giving diets high in sucrose and dextrin (61%) during either the pre-initiation, the initiation, and/or the post-initiation stage of the ACF development. The colonic cell proliferation, activity of colonic phase II enzymes, and a biomarker of lipid peroxidation were additionally examined in order to obtain information on the specific mechanisms involved in the suggested effect of sucrose and dextrin on ACF development. The number of large sized and the total number of ACF were significantly increased by feeding sucrose and dextrin in the post-initiation period. No positive association between colonic cell proliferation and ACF was seen. The level of oxidative stress in the cytosol from the proximal colon and colonic glutathione transferase and quinone reductase was not affected by the sugar treatments. The overall results from this study show that sucrose and dextrin enhance the number of preneoplastic lesions in AOM-initiated rats, and act primarily as promoters in the development of ACF.
Diabetes | 2014
Carsten F. Gotfredsen; Anne-Marie Mølck; Inger Thorup; Niels C. Berg Nyborg; Zaki Salanti; Lotte Bjerre Knudsen; Marianne O. Larsen
Increased pancreas mass and glucagon-positive adenomas have been suggested to be a risk associated with sitagliptin or exenatide therapy in humans. Novo Nordisk has conducted extensive toxicology studies, including data on pancreas weight and histology, in Cynomolgus monkeys dosed with two different human glucagon-like peptide-1 (GLP-1) receptor agonists. In a 52-week study with liraglutide, a dose-related increase in absolute pancreas weight was observed in female monkeys only. Such dose-related increase was not found in studies of 4, 13, or 87 weeks’ duration. No treatment-related histopathological abnormalities were observed in any of the studies. Quantitative histology of the pancreas from the 52-week study showed an increase in the exocrine cell mass in liraglutide-dosed animals, with normal composition of endocrine and exocrine cellular compartments. Proliferation rate of the exocrine tissue was low and comparable between groups. Endocrine cell mass and proliferation rates were unaltered by liraglutide treatment. Semaglutide showed no increase in pancreas weight and no treatment-related histopathological findings in the pancreas after 13 or 52 weeks’ dosing. Overall, results in 138 nonhuman primates showed no histopathological changes in the pancreas associated with liraglutide or semaglutide, two structurally different GLP-1 receptor agonists.
Experimental and Toxicologic Pathology | 2011
Henning Hvid; Inger Thorup; Martin B. Oleksiewicz; Ingrid Sjögren; Henrik Elvang Jensen
In toxicopathological studies of the rat mammary glands, the guidelines of the Registry of Industrial Toxicology and Animal Data (RITA) recommend transverse sections of the inguinal mammary gland. However, occasionally limited amounts of mammary gland tissue are found in transverse sections. We compared transverse sectioning with an alternative method comprising horizontal sections of the rat mammary glands. Normal cycling female Sprague Dawley rats were sacrificed in proestrous, estrous, metestrous and diestrous, and samples from all mammary glands were collected. Transverse sections were prepared from the left-sided glands, and horizontal sections were cut from the right-sided glands. Sections were stained with HE, and epithelial and myoepithelial cells were visualized by immunohistochemical staining of cytokeratin 18 and alpha smooth muscle actin, respectively. Area of the mammary fat pad, mammary epithelium and connective tissue were measured in randomly sampled vision fields from each section. Horizontal sections contained a significantly larger area of mammary fat pad as well as glandular and connective tissue. No differences in tissue densities of epithelial or myoepithelial cells or connective tissue were observed between transverse sections and horizontal sections. Interestingly, densities of epithelium and connective tissue varied between cranial and caudal glands as well as the phases of the estrous cycle. In conclusion, horizontal histological sections of the rat mammary gland provided significantly larger samples of mammary gland tissue with no difference in tissue composition compared to transverse sections, which are recommended in the RITA guidelines.
Experimental and Toxicologic Pathology | 2012
Henning Hvid; Inger Thorup; Ingrid Sjögren; Martin B. Oleksiewicz; Henrik Elvang Jensen
Assessment of mammary gland proliferation in rats is an important endpoint in preclinical safety studies of pharmaceutical compounds. However, existing data on mammary gland proliferation in rats during the estrous cycle is conflicting, and it is unknown whether mammary gland proliferation differs between young and mature female virgin rats. Additionally, it is unclear which of the commonly applied markers of proliferating cells that is optimal for assessment of rat mammary gland proliferation. In this study the caudal thoracic, the abdominal and the cranial inguinal (i.e., the 3rd the 4th and the 5th) mammary gland were collected from 29 young and 26 mature non-treated, virgin female Sprague Dawley rats. Estrous cycle stage was determined from repeated vaginal smears and histological examination of the reproductive organs. Proliferation of mammary epithelium was assessed by immunohistochemistry using three markers: PCNA, Ki67, and BrdU. Proliferation of the mammary epithelium occurred mainly in the terminal end buds in the young animals. Epithelial proliferation was significantly increased during metestrus compared to the other phases. Mammary gland proliferation in pseudo-pregnant females was increased compared to proestrus, estrus and diestrus, but not metestrus. Except during estrus no difference in mammary gland proliferation was observed between young and mature female rats, and no significant differences was observed between different mammary glands. The percentages of PCNA-, Ki67- and BrdU-positive epithelial cells were significantly correlated. In conclusion, the variation in normal proliferation between estrous cycle stages and animals with an irregular estrous cycle should be considered in toxico-pathological studies of mammary gland proliferation.
Toxicologic Pathology | 2011
Henning Hvid; Johannes Josef Fels; Rikke Kaae Kirk; Inger Thorup; Henrik Elvang Jensen; Bo Falck Hansen; Martin B. Oleksiewicz
High doses of insulin and the insulin analog AspB10 have been reported to increase mammary tumor incidence in female rats likely via receptor-mediated mechanisms, possibly involving enhanced IGF-1 receptor activation. However, insulin and IGF-1 receptor functionality and intracellular signaling in the rat mammary gland in vivo is essentially unexplored. The authors investigated the effect of a single subcutaneous dose of 600 nmol/kg human insulin or IGF-1 on Akt and ERK1/2 phosphorylation in rat liver, colon, and mammary gland. Rat tissues were examined by Western blotting and immunohistochemistry by phosphorylation-specific antibodies. Insulin as well as IGF-1 caused Akt phosphorylation in mammary epithelial cells, with myoepithelial and basal epithelial cells being most sensitive. IGF-1 caused stronger Akt phosphorylation than insulin in mammary gland epithelial cells. Phosphorylation of ERK1/2 was not influenced by insulin or IGF-1. Rather, in liver and mammary gland P-ERK1/2 appeared to correlate with estrous cycling, supporting that ERK1/2 has important physiological roles in these two organs. In short, these findings supported that the rat mammary gland epithelium expresses functional insulin and IGF-1 receptors and that phosphorylation of Akt as well as ERK1/2 may be of value in understanding the effects of exogenous insulin in the rat mammary gland and colon.
Journal of Applied Toxicology | 2011
Henning Hvid; Robert Klopfleisch; Sara Vienberg; Bo Falck Hansen; Inger Thorup; Henrik Elvang Jensen; Martin B. Oleksiewicz
Supra‐pharmacological doses of the insulin analog X10 (AspB10) increased the incidence of mammary tumors in female Sprague–Dawley rats in chronic toxicity studies, most likely via receptor‐mediated mechanisms. However, little is known about the expression of the insulin receptor family in the rat mammary gland. Using laser micro‐dissection, quantitative RT‐PCR and immunohistochemistry, we examined the expression of IR (insulin receptor), IGF‐1R (IGF‐1 receptor), IRR (insulin receptor‐related receptor), ERα (estrogen receptor alpha), ERβ (estrogen receptor beta) and PR (progesteron receptor) in young, virgin, female Sprague–Dawley rats and compared to expression in reference organs. The mammary gland displayed the highest expression of IRR and IGF‐1R. In contrast, low expression of IR transcripts was observed in the mammary gland tissue with expression of the IR‐A isoform being 5‐fold higher than the expression of the IR‐B. By immunohistochemistry, expression of IR and IGF‐1R was detected in all mammary gland epithelial cells. Expression of ERα and PR was comparable between mammary gland and ovary, whereas expression of ERβ was lower in mammary gland than in the ovary. Finally, expression of IGF‐1R and PR in the mammary gland varied during the estrous cycle. These findings are important for the understanding of carcinogenic effects of insulin analogs in the rat mammary gland, and relevant for development of refined short‐term models for preclinical safety assessment of insulin analogs. Copyright
Toxicologic Pathology | 2018
Jennifer M. Rojas; Florian Bolze; Inger Thorup; Jette Nowak; Charlotte M. Dalsgaard; Mikala Skydsgaard; Line Olrik Berthelsen; Kevin A. Keane; Henrik Søeborg; Ingrid Sjögren; Jes Tovborg Jensen; Johannes Josef Fels; Hanne Offenberg; Lærke W. Andersen; Majken Dalgaard
The obese rodent serves as an indispensable tool for proof-of-concept efficacy and mode-of-action pharmacology studies. Yet the utility of this disease model as an adjunct to the conventional healthy animal in the nonclinical safety evaluation of anti-obesity pharmacotherapies has not been elucidated. Regulatory authorities have recommended employing disease models in toxicology studies when necessary. Our study investigated standard and exploratory toxicology parameters in the high-fat diet (HFD)-induced obese, polygenic Sprague-Dawley rat model in comparison to chow diet (CD)-fed controls. We sought to establish feasibility of the model for safety testing and relevance to human obesity pathophysiology. We report that both sexes fed a 45% kcal HFD for 29 weeks developed obesity and metabolic derangements that mimics to a certain extent, common human obesity. Minor clinical pathologies were observed in both sexes and considered related to CD versus HFD differences. Histopathologically, both sexes exhibited mild obesity-associated findings in brown and subcutaneous white fat, bone, kidneys, liver, lung, pancreas, salivary parotid glands, and skeletal muscle. We conclude that chronic HFD feeding in both sexes led to the development of an obese but otherwise healthy rat. Therefore, the diet-induced obese Sprague-Dawley rat may serve as a suitable model for evaluating toxicity findings encountered with anti-obesity compounds.