Niels Vrang

Wisconsin National Primate Research Center, Madison, Wisconsin, United States

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Publications (86)362.47 Total impact

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    ABSTRACT: Neuromedin U (NMU) is a 25 amino acid peptide expressed and secreted in the brain and gastrointestinal tract. Data have shown that peripheral administration of human NMU decreases food intake and body weight and improves glucose tolerance in mice, suggesting that NMU receptors constitute a possible anti-diabetic and anti-obesity drug target. However, the clinical use of native NMU is hampered by a poor pharmacokinetic profile. In the current study, we report in vitro and in vivo data from a series of novel lipidated NMU analogs.In vitro plasma stability studies of native NMU were performed to investigate the proteolytic stability and cleavage sites using LC–MS. Native NMU was found to be rapidly cleaved at the C-terminus between Arg24 and Asn25, followed by cleavage between Arg16 and Gly17. Lipidated NMU analogs were generated using solid-phase peptide synthesis, and in vitro potency was investigated using a human embryonic kidney 293-based inositol phosphate accumulation assay. All lipidated analogs had preserved in vitro activity on both NMU receptors with potency improving as the lipidation site was moved away from the receptor-interacting C-terminal octapeptide segment.In vivo efficacy was assessed in lean mice as reduction in food intake after acute subcutaneous administration of 1, 0.3, 0.1, and 0.03 µmol/kg. These lipidated NMU analogs prolonged the anorectic effect of NMU in a dose-dependent manner. This was likely an effect of improved pharmacokinetic properties because of improved vitro plasma stability. Accordingly, the data demonstrate that lipidated NMU analogs may represent drug candidates for the treatment of obesity. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
    Journal of Peptide Science 12/2014; DOI:10.1002/psc.2727 · 1.86 Impact Factor
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract (NTS) where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been mapped in the rodent brain, but no studies have described the distribution of GLP-1Rs in the nonhuman primate central nervous system. Here, we characterized the distribution of GLP-1R mRNA and protein in the adult macaque brain using in situ hybridization, radioligand receptor autoradiography and immunohistochemistry with a primate specific GLP-1R antibody. Immunohistochemistry demonstrated that the GLP-1R is localized to cell bodies and fiber terminals in a very selective distribution throughout the brain. Consistent with the functional role of the GLP-1R system, we find the highest concentration of GLP-1R-immunoreactivity present in select hypothalamic and brainstem regions that regulate feeding including the paraventricular and arcuate hypothalamic nuclei, as well as the area postrema, NTS, and dorsal motor nucleus of the vagus. Together, our data demonstrate that GLP-1R distribution is highly conserved between rodent and primate although a few key species differences were identified including the amygdala where GLP-1R expression is much higher in primate than in rodent.
    Endocrinology 11/2014; DOI:10.1210/en.2014-1675 · 4.72 Impact Factor
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    ABSTRACT: Liraglutide is a glucagon-like peptide-1 (GLP-1) analog marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide also reduces body weight. It is not fully understood how liraglutide induces weight loss or to what degree liraglutide acts directly in the brain. Here, we determined that liraglutide does not activate GLP-1–producing neurons in the hindbrain, and liraglutide-dependent body weight reduction in rats was independent of GLP-1 receptors (GLP-1Rs) in the vagus nerve, area postrema, and paraventricular nucleus. Peripheral injection of fluorescently labeled liraglutide in mice revealed the presence of the drug in the circumventricular organs. Moreover, labeled liraglutide bound neurons within the arcuate nucleus (ARC) and other discrete sites in the hypothalamus. GLP-1R was necessary for liraglutide uptake in the brain, as liraglutide binding was not seen in Glp1r–/– mice. In the ARC, liraglutide was internalized in neurons expressing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART). Electrophysiological measurements of murine brain slices revealed that GLP-1 directly stimulates POMC/CART neurons and indirectly inhibits neurotransmission in neurons expressing neuropeptide Y (NPY) and agouti-related peptide (AgRP) via GABA-dependent signaling. Collectively, our findings indicate that the GLP-1R on POMC/CART-expressing ARC neurons likely mediates liraglutide-induced weight loss.
    Journal of Clinical Investigation 10/2014; 124(10-10):0-0. DOI:10.1172/JCI75276 · 13.77 Impact Factor
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    ABSTRACT: Linagliptin is a dipeptidyl peptidase (DPP)-IV inhibitor approved for the treatment of type 2 diabetes. DPP-IV inhibitors are considered weight neutral, suggesting that elevation of endogenous incretin levels is not sufficient to promote weight loss per se. Here we evaluated the effect of linagliptin in combination with subcutaneous treatment of GLP-1(7-36) on body weight regulation in diet-induced obese (DIO) rats. Linagliptin administered perorally (1.5mg/kg, b.i.d.), but not subcutaneously (0.5mg/kg, b.i.d.), evoked a very modest body weight loss (2.2%) after 28 days of treatment. GLP-1 (0.5mg/kg, s.c.) treatment alone induced a body weight loss of 4.1%. In contrast, combined linagliptin (1.5mg/kg, p.o., or 0.5mg/kg, s.c.) and GLP-1 (0.5mg/kg) treatment evoked a marked anorectic response with both routes of linagliptin administration being equally effective on final body weight loss (7.5-8.0%). In comparison, liraglutide monotherapy (0.2mg/kg, s.c., b.i.d.) reduced body weight by 10.1%. Interestingly, the weight lowering effect of combined linagliptin and GLP-1 treatment was associated with a marked increase in chow preference, being more pronounced as compared to liraglutide treatment. In addition, linagliptin and GLP-1 co-treatment, but not liraglutide, specifically increased prepro-dynorphin mRNA levels in the caudate-putamen, an effect not obtained with administration of the compounds individually. In conclusion, co-treatment with linagliptin and GLP-1 synergistically reduces body weight in obese rats. The anti-obesity effect was caused by appetite suppression with a concomitant change in diet preference, which may potentially be associated with increased dynorphin activity in forebrain regions involved in reward anticipation and habit learning.
    European Journal of Pharmacology 08/2014; 741. DOI:10.1016/j.ejphar.2014.08.010 · 2.68 Impact Factor
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    ABSTRACT: Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and anti-diabetic efficacy. Through an insulin and β-cell independent mechanism, empagliflozin, a specific sodium glucose co-transporter type-2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the anti-diabetic durability of empagliflozin treatment (10 mg/kg, p.o.) against glibenclamide (3 mg/kg, p.o.) and liraglutide (0.2 mg/kg, s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic Fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and HbA1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared to week 4, those of empagliflozin remained stable throughout the study period. Similarly, empagliflozin improved glucose tolerance and preserved insulin secretion after both 4 and 8 weeks of treatment. These effects were reflected by a less reduction in β-cell mass with empagliflozin or liraglutide at week 4, while only empagliflozin showed β-cell sparing effects at week 8. While this study cannot be used to dissociate the absolute anti-diabetic efficacy among those different mechanisms of action, the study demonstrates that empagliflozin exerts a more sustained improvement of glucose homeostasis and β-cell protection ZDF rats. In comparison to other type 2 diabetic treatments, SGLT-2 inhibitors may through insulin-independent pathways thus enhance durability of β-cell protection and anti-diabetic efficacy.
    Journal of Pharmacology and Experimental Therapeutics 07/2014; 350(3). DOI:10.1124/jpet.114.213454 · 3.86 Impact Factor
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    ABSTRACT: Anti-diabetic treatments aiming to preserve or even to increase beta 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, on glycemic control, beta 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 HbA1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of beta 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 beta cell mass after 4 and 8 weeks treatment, whereas the effect of liraglutide was transient. The expansion in beta cell mass observed in the ZP3022 treated mice appeared to be driven by an increased beta 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 demonstrates that the GLP-1-gastrin dual agonist, ZP3022, causes a sustained improvement in glycemic control accompanied by an increase in beta cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases beta cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of anti-diabetic treatments.
    Journal of Pharmacology and Experimental Therapeutics 06/2014; 350(2). DOI:10.1124/jpet.114.215293 · 3.86 Impact Factor
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    ABSTRACT: Stimulation of the G protein coupled receptor GPR120 has been shown to have anti-inflammatory and insulin-sensitizing effects, to promote glucagon like peptide-1 (GLP-1) secretion, and to play a key role in sensing dietary fat and control energy balance. In a search for differentially expressed genes potentially involved in food intake and body-weight regulation we identified GPR120 to be differentially regulated in the intestine of selectively bred diet induced obese (DIO) and diet resistant (DR) rats. Subsequently we investigated the effect of GPR120 receptor stimulation with the long chain fatty acid alpha linolenic acid (ALA) on GLP-1 secretion in rats. Independent of diet (high or low fat), GPR120 expression showed a two-fold increase in the intestine of DIO compared to DR rats. In situ hybridization revealed a broad expression of GPR120 in the gut mucosa in both intestinal epithelial and endocrine cells. Using double in situ hybridization GPR120 mRNA did not appear to be enriched in preproglucagon expressing L-cells. In line with the anatomical data, ALA administration did not increase circulating GLP-1 levels. Our data shows a widespread expression of GPR120 in the gut epithelium and can not confirm a major role for GPR120 in the regulation of GLP-1 secretion. The broad expression of GPR120 in the gut epithelium supports reports indicating a putative role of GPR120 as a sensor of dietary fat.
    PLoS ONE 02/2014; 9(2):e88227. DOI:10.1371/journal.pone.0088227 · 3.53 Impact Factor
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    ABSTRACT: Aim To investigate the short-term effect of ileal interposition (IT) surgery on gut morphology and enteroendocrine cell numbers in the pre-diabetic Uc Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat. Study Design Two-month old male UCD-T2DM rats underwent either sham (n = 5) or IT (n = 5) surgery. Intestines were collected 1.5 months after surgery. The jejunum, ileum and colon regions were processed for histochemical and immunohistochemical labeling and stereological analyses of changes in gut morphometry and number of enteroendocrine cells. Results Stereological analysis of intestinal volume, luminal surface area and the number of all chromogranin A-positive enteroendocrine cells were markedly increased in the IT rats compared with sham-operated animals. Subanalyses of the glucagon-like peptide 2, cholecystokinin, serotonin cells and the neurotensin immunoreactive sub-pool of enteroendocrine cells in the IT region revealed an increase in numbers across phenotypes. However, the density of the different cell types varied. Conclusion IT surgery in the UCD-T2DM rat leads to rapid alterations in gut morphometry and an increase in the number of enteroendocrine cells. This effect may potentially explain why IT surgery delays the onset of type 2 diabetes in the UCD-T2DM rat.
    Regulatory Peptides 02/2014; DOI:10.1016/j.regpep.2014.01.002 · 2.01 Impact Factor
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    ABSTRACT: To characterise changes in pancreatic beta cell mass during the development of diabetes in untreated male C57BLKS/J db/db mice. Blood samples were collected from a total of 72 untreated male db/db mice aged 5, 6, 8, 10, 12, 14, 18, 24 and 34 weeks, for measurement of terminal blood glucose, HbA1c, plasma insulin, and C-peptide. Pancreata were removed for quantification of beta cell mass, islet numbers as well as proliferation and apoptosis by immunohistochemistry and stereology. Total pancreatic beta cell mass increased significantly from 2.1 ± 0.3 mg in mice aged 5 weeks to a peak value of 4.84 ± 0.26 mg (P < 0.05) in 12-week-old mice, then gradually decreased to 3.27 ± 0.44 mg in mice aged 34 weeks. Analysis of islets in the 5-, 10-, and 24-week age groups showed increased beta cell proliferation in the 10-week-old animals whereas a low proliferation is seen in older animals. The expansion in beta cell mass was driven by an increase in mean islet mass as the total number of islets was unchanged in the three groups. The age-dependent beta cell dynamics in male db/db mice has been described from 5-34 weeks of age and at the same time alterations in insulin/glucose homeostasis were assessed. High beta cell proliferation and increased beta cell mass occur in young animals followed by a gradual decline characterised by a low beta cell proliferation in older animals. The expansion of beta cell mass was caused by an increase in mean islet mass and not islet number.
    PLoS ONE 12/2013; 8(12):e82813. DOI:10.1371/journal.pone.0082813 · 3.53 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Diabetes care 12/2013; 36(12):e213. DOI:10.2337/dc13-1134 · 7.74 Impact Factor
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    ABSTRACT: Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal. The full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells. RYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell. Collectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB.
    PLoS ONE 06/2013; 8(6):e65696. DOI:10.1371/journal.pone.0065696 · 3.53 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    American Journal of Translational Research 01/2013; 5(3):347-58. · 3.23 Impact Factor
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    ABSTRACT: Post-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT) surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT) and serial oral glucose tolerance tests (OGTT). Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1) secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that post-operative increases in circulating cholic acid concentration contribute to improvements in glucose homeostasis after IT surgery by ameliorating ER stress.
    Disease Models and Mechanisms 12/2012; DOI:10.1242/dmm.010421 · 4.96 Impact Factor
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    ABSTRACT: It has been hypothesized that amphipathic peptides might bind to membranes prior to activating their cognate receptors, but this has proven difficult to test. The peptide hormone PYY3-36 is believed to perform its appetite-suppressing actions through binding to hypothalamic Y2 receptors. It has been proposed that PYY3-36 via its amphipathic α-helix binds to the plasma membrane prior to receptor docking. Here, our aim was to study the implication of this hypothesis using new analogs of PYY3-36. We first studied membrane binding of PYY3-36. Next, we designed a series of PYY3-36 analogs to increase membrane-binding affinity by substituting the N-terminal segment with a de novo designed α-helical, amphipathic sequence. These 2-helix variants of PYY3-36 were assembled by solid-phase peptide synthesis. Pharmacological studies demonstrated that even though the native peptide sequence was radically changed, highly active Y2 receptor agonists were generated. A potent analog, with a Kd of 4 nM for membranes, was structurally characterized by NMR in the membrane-bound state, which clearly showed that it formed the expected 2-helix. The topology of the peptide-micelle association was studied by paramagnetic relaxation enhancement using a spin label, which confirmed that the hydrophobic residues bound to the membrane. Our studies further support the hypothesis that PYY3-36 associates with the membrane and indicate that this can be used in the design of novel molecules with high receptor binding potency. These observations are likely to be generally important for peptide hormones and biopharmaceutical drugs derived from them. This new 2-helix variant of PYY3-36 will be useful as a tool compound for studying peptide-membrane interactions.
    Journal of Peptide Science 09/2012; 18(9):579-87. DOI:10.1002/psc.2436 · 1.86 Impact Factor
  • Regulatory Peptides 08/2012; 177:S29. DOI:10.1016/j.regpep.2012.05.062 · 2.01 Impact Factor
  • Regulatory Peptides 08/2012; 177:S18. DOI:10.1016/j.regpep.2012.05.028 · 2.01 Impact Factor
  • Regulatory Peptides 08/2012; 177:S21–S22. DOI:10.1016/j.regpep.2012.05.038 · 2.01 Impact Factor
  • Regulatory Peptides 08/2012; 177:S22. DOI:10.1016/j.regpep.2012.05.039 · 2.01 Impact Factor
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    ABSTRACT: 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 non-diabetic vehicle-treated mice (P<0.01 for both) but were greatly reduced in diabetic mice irrespective of treatment. No changes were seen in the α, δ and γ 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.
    Journal of Endocrinology 07/2012; 214(3):381-7. DOI:10.1530/JOE-11-0479 · 3.59 Impact Factor
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    ABSTRACT: 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.
    AJP Endocrinology and Metabolism 05/2012; 303(2):E253-64. DOI:10.1152/ajpendo.00182.2012 · 4.51 Impact Factor

Publication Stats

4k Citations
362.47 Total Impact Points


  • 2014
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
  • 2012
    • Boehringer Ingelheim Veterinary Research Center Gmbh & Co. Kg
      Hanover, Lower Saxony, Germany
  • 2001–2002
    • Center for Clinical and Basic Research
      København, Capital Region, Denmark
  • 1994–1999
    • IT University of Copenhagen
      København, Capital Region, Denmark